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Significant progress in understanding cancer pathogenesis, it remains one of the leading causes of death after cardiovascular diseases. Similarly viral infections have emerged from wildlife or re-emerged, generating serious threats to the global health. As a result, there is an urgent need for the development of novel, more effective anticancer and antiviral therapeutics. Scientists, medicinal chemists and researchers are continuously finding novel targets, mechanisms and molecules against theses severe and dangerous infections. Therefore, ongoing extensively study and research emphasizes 1,3,4 thiadiazole pharmacophore have versatile pharmacological actions. Due to mesoionic behaviour of 1,3,4 thiadiazole pharmacophore allows to enter and easily cross biological membrane which allow to interact various biological proteins. In this review study an attempt has been made of various mechanisms involved in cancer and viral prevalence with updated studies done so far. This review study also findings the role of 1,3,4 thiadiazole motif in the management of various cancers and viral infection. This study also highlighting research statics on clinical trials and various patents containing 1,3,4 thiadiazole derivatives. © 2022 The Author(s)
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Background: In first line (L1) for EGFR-mutated (mEGFR) advanced NSCLC (aNSCLC), osimertinib (osi) has been the preferred option since 2018. First generation anti-EGFR TKI (1G) alone followed by osi, or 1G + anti-angiogenic or 1G + chemotherapy are other options. We aimed to assess the subgroups of patients (pts) that do not benefit from 1G alone compared with osimertinib L1 in mEGFR aNSCLC. Methods: Retrospective international study including pts with mEGFR aNSCLC treated with either osi or the sequence of 1G followed by osi (seq group). Primary endpoint was the PFS of the global strategy (PFSglob) defined as the time between L1 start and progression after L2 treatment or death. Subgroups analyses included pts with high tumour burden (high-TM;> 3 metastatic sites and/or central nervous system (CNS) involvement), poor performance status (PS), and T790M negative (seq subgroup only). Results: A total of 235 pts were included: 104 in the seq group, 118 in the osi L1 group. 15 had T790M negative at PD after 1G, they received osi as a therapeutic test. From these pts, 222 had an exon19 or 21 EGFR mut, 13 had uncommon mEGFR. Mean age was 65 years, 64% were female, and 60% never smokers. Pts from the osi L1 group had poorer PS (23% vs 10%), higher rate of co-mutations (23% vs 19%) and more CNS involvement (47% vs 19%). After a median (m) follow up of 30.6 months in the exon 19 and 21 population, mPFSglob was 27.4 mo (23.0-31.0) and mPFS L1 was 15.5mo (13.7-18.4) Table. The sequence was associated with shorter PFS L1 compared with osi L1 particularly in high-TM (10.5 mo vs 17.1 mo, p<0.0001);PFS was numerically shorter in poor PS (≥2) population (11.0 mo vs 15.6 mo, p=0.1). [Formula presented] Conclusions: 1G TKI followed by osi seemed to be detrimental compared with os L1 for pts with high-TM or poor PS mEGFR aNSCLC. In this population, the intensification of L1 treatment with osimertinib or a combination of 1G with anti-angiogenic or chemotherapy could be the better option in the first-line setting. Updated results will be presented at the congress. Legal entity responsible for the study: Institut Gustave Roussy. Funding: Has not received any funding Disclosure: E. Auclin: Financial Interests, Personal, Advisory Board: Sanofi, Amgen. N. Girard: Financial Interests, Personal, Invited Speaker: AstraZeneca, BMS, MSD, Roche, Pfizer, Mirati, Amgen, Novartis, Sanofi;Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, MSD, Roche, Pfizer, Janssen, Boehringer, Novartis, Sanofi, AbbVie, Amgen, Lilly, Grunenthal, Takeda, Owkin;Financial Interests, Institutional, Research Grant, Local: Roche, Sivan, Janssen;Financial Interests, Institutional, Funding: BMS;Non-Financial Interests, Officer, International Thymic malignancy interest group, president: ITMIG;Other, Other, Family member is an employee: AstraZeneca. M.T. Moran Bueno: Financial Interests, Personal, Advisory Board, Advisory Role: AstraZeneca, Boehringer Ingelheim, BMS;Financial Interests, Personal, Advisory Board, Advisory role: Roche. B. Besse: Financial Interests, Institutional, Funding: 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi Sankyo, Eli Lilly, GSK, Janssen, Onxeo, Ose Immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals;Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical, EISAI, Genzyme Corporation, Inivata, Ipsen, Turning Point Therapeutics. L. Mezquita: Financial Interests, Personal, Advisory Board: Takeda, AstraZeneca, Roche;Financial Interests, Personal, Invited Speaker: Roche, BMS, AstraZeneca, Takeda;Financial Interests, Personal, Research Grant, SEOM Beca Retorno 2019: BI;Financial Interests, Personal, Research Grant, ESMO TR Research Fellowship 2019: BMS;Financial Interests, Institutional, Research Grant, COVID research Grant: Amgen;Financial Interests, Institutional, Invited Speaker: Inivata, Stilla. All other authors have declared no conflicts of interest.
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Introduction: Osimertinib is a selective third-generation EGFR-TKI inhibitor with an inhibitory effect on the T790M mutation. Interstitial lung disease (ILD) occurred in 3.9% of the Osimertinib-treated patients (with 0.4% fatal cases). Methods: Case report of fatal ILD induced by Osimertinib in a patient with metastatic lung adenocarcinoma. Results: We present the case of an 81-year-old female patient diagnosed with stage IVB lung adenocarcinoma (May 2020) with pulmonary, adrenal, and brain metastasis. Genetic sequencing showed an exon 19 deletion. She started erlotinib until documentation of disease progression in January 2021. In this context, she performed a liquid biopsy with the detection of a T790M resistance mutation. She started Osimertinib in February 2021. Her past medical history showed diabetes and dyslipidemia. Two months after starting Osimertinib, she went to the emergency department (ER) with a one-week evolution with progressive dyspnea, cough, and fever. Upon admission to the ER, she was conscious and cooperative, with respiratory distress signs, normal blood pressure, and hypoxemia. She had decreased breath sounds, and coarse crackles were audible bilaterally. In the blood sampling, Haemoglobin was 7.7 mmol/L, creatinine 0.08 mmol/L, platelets 257000x10ˆ9/L, C-reactive protein 28.6 nmol/L, and NT-proBNP 98 pmol/L. Rt-PCR for sars-CoV-2 detection was negative. X-ray showed bilateral diffuse infiltrates. She started oxygen therapy via nasal cannula at 3l/min and IV antibiotics. ABG values were pH 7.44, pCO2 37 mmHg, pO2 69 mmHg, HCO3 26 mEq/L, sO2 94%. On reassessment after 3 hours, she presented worsening dyspnea and dizziness, with higher oxygen needs (venturi mask, 60%). Chest CT angiography showed extensive bilateral diffuse ground-glass densification with crazy-paving areas. It also showed no signs of pulmonary embolism. We admitted her to a level 2 ICU unit for surveillance. Due to suspected drug toxicity, she started Methylprednisolone pulses (1000mg/3days). Six hours after admission, due to hypoxemia worsening, non-invasive ventilation was started with the need to escalate oxygen therapy to 100% FiO2. At 24h, she showed clinical and blood analysis improvement. Nonetheless, she still needed 100% fiO2 to maintain >92% oxygen saturation. On the 4th day of hospitalization, she was hypotensive, prostrated, and with little reaction to painful stimulation. She started palliative treatment and died on the same day. Conclusions: ILD is a rare adverse effect of the treatment with Osimertinib, and fatal ILD is even rarer. The time from starting Osimertinib to this side effect is variable between patients. Awareness is necessary for a rapid diagnosis and early treatment. [Formula presented] Keywords: Osimertinib, Intersticial Lung Disease, Adverse effect
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BACKGROUND: Patients diagnosed with non-small-cell lung cancer with activated epidermal growth factor receptor mutations are more likely to develop leptomeningeal (LM) metastasis than other types of lung cancers and have a poor prognosis. Early diagnosis and effective treatment of leptomeningeal carcinoma can improve the prognosis. CASE SUMMARY: A 55-year-old female with a progressive headache and vomiting for one month was admitted to Peking University First Hospital. She was diagnosed with lung adenocarcinoma with osseous metastasis 10 months prior to admittance. epidermal growth factor receptor (EGFR) mutation was detected by genomic examination, so she was first treated with gefitinib for 10 months before acquiring resistance. Cell-free cerebrospinal fluid (CSF) circulating tumor DNA detection by next-generation sequencing was conducted and indicated the EGFR-Thr790Met mutation, while biopsy and cytology from the patient's CSF and the first enhanced cranial magnetic resonance imaging (MRI) showed no positive findings. A month later, the enhanced MRI showed linear leptomeningeal enhancement, and the cytology and biochemical examination in CSF remained negative. Therefore, osimertinib (80 mg/d) was initiated as a second-line treatment, resulting in a good response within a month. CONCLUSION: This report suggests clinical benefit of osimertinib in LM patients with positive detection of the EGFR-Thr790Met mutation in CSF and proposes that the positive findings of CSF circulating tumor DNA as a liquid biopsy technology based on the detection of cancer-associated gene mutations may appear earlier than the imaging and CSF findings and may thus be helpful for therapy. Moreover, the routine screening of chest CT with the novel coronavirus may provide unexpected benefits.
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After the introduce of new treatment options is always important to see how the results of the registered studies will be putted into routine clinical practice. Clinical studies help to assess the efficacy and safety of therapy and to conduct the objective comparison of the current standard of treatment. However, it is impossible to take into account all the variety of situations that oncologists can face in their daily work. Nowadays, the use of targeted therapy in the presence of the specific genetic disorders, in particular, driver mutations in the epidermal growth factor receptor (EGFR) gene, is an integral part of the management of patients with advanced non-small cell lung cancer (NSCLC). The first EGFR tyrosine kinase inhibitors (TKIs) have significantly changed our possibility of the treatment in this group of patients, and today we are already using the third-generation EGFR TKIs. The review analyzes the experience of using the third-generation EGFR TKIs – osimertinib, through the prism of questions, asking by the practitioners: evaluation of the efficacy of treatment in routine practice, the management of difficult patients, in particular, the patients with bone and brain metastases, the patients with multiple primary tumors, the management tactics of patient taking into account the COVID-19 pandemic and related treatment interruptions. The literature and international experience review is completed by clinical cases from different regions of the Russian Federation. © 2022 Consilium Medikum. All Rights Reserved.
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Introduction COVID-19 disease has caused a global health and economic crisis. The introduction of the different COVID-19 vaccines has resulted in a significant decrease in the morbidity and mortality associated with this disease. Adverse effects have been reported, including cardiological ones such as myocarditis or pericarditis after administration. Likewise, tyrosine kinase inhibitor drugs such as osimertinib used in lung cancer patients with epidermal growth factor receptor (EGFR) mutation are associated with heart failure or prolongation of the QT interval. Case report 62-year-old woman diagnosed in September 2019 of lung adenocarcinoma stage IV with bilateral lung and lymph node involvement, carrier of an EGFR mutation (Ex19Del) on treatment with osimertinib. She attended emergency department for fever and hypotension 24 h after administration of the third dose of Moderna® COVID-19 vaccine in the context of acute myocarditis with evidence of severe left ventricular (LV) dysfunction in cardiogenic shock. She required vasoactive support, non-invasive mechanical ventilation, corticotherapy, immunoglobulins and subsequent ventricular support with Impella, with improvement of the clinical picture after 3 days. Cardiac magnetic resonance imaging (MRI) showed evidence of global myocardial oedema compatible with acute myocarditis. Coronary CT showed a lesion in the anterior descending coronary artery requiring revascularization. A few days later, she presented febrile symptoms with isolation of Staphylococcus aureus in the central line catheter and antibiotherapy with cloxacillin was started, with subsequent resolution of the infectious symptoms. Conclusion This is an exceptional and controversial case of fulminant myocarditis probably related to the Modern COVID-19 vaccine in a patient diagnosed with metastatic lung adenocarcinoma on treatment with osimertinib. An increasing number of cases of myocarditis and pericarditis have been reported following vaccination with COVID-19 mRNA vaccines. In addition, retrospective data have shown an increased risk of QT prolongation and heart failure in patients treated with tyrosine kinase inhibitors. Hence, the need for close monitoring of cardiac function during treatment of these patients. Future studies will be necessary to evaluate unknown adverse reactions of these vaccines and their possible interaction with other antineoplastic drugs.
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Despite the many challenges faced in 2020, we have seen impressive progress in many areas of cancer research. Twenty-one novel oncology drugs were approved by the U.S. Food and Drug Administration (FDA). Although cancer is one of the major public health problems worldwide, cancer mortality projections for 2021 confirm the persistent declines in cancer mortality in EU and US for many specific cancers. The breast cancer treatment landscape has evolved in the past year and several new drugs approved in 2020 as antibody drugs conjugates (ADC) sacituzumab in TNBC and fam-trastuzumab deruxtecan-nxki (T-DXd) in metastatic HER2 positive BC, as well as tucatinib, a small kinase inhibitor. A few very important clinical trial /RxPONDER, ADAPT, PRIME II/ presented last year support de-escalation of adjuvant chemotherapy and radiation, sparing patients from some of the side effects that can accompany treatments. In ovarian cancer five-year follow-up data from the SOLO-1 trial continue to show progression-free survival benefit of olaparib as maintenance therapy following platinum-based chemotherapy in the frontline setting. In the final analysis of SOLO-2 trial, maintenance olaparib provided an improvement of 12.9 months in median OS vs placebo in women with relapsed BRCA-related ovarian cancer who had responded to their most recent platinum-based chemotherapy after having received at least one more line of chemotherapy.In 2020 first new treatment for hepatocellular carcinoma approved in more than ten years according to the data from phase III IMbrave 150 trial. In that study, which includes 501 patients the combination of atezolizumab and bevacizumab provides the longest survival seen in a front-line phase III study in advanced HCC, confirming atezo + bev as a standard of care for previously untreated, unresectable HCC.In the field of thoracic oncology there were some very important news in 2020, potentially practice changing. Osimertinib, next generation EGFR-TKI, standard first line therapy in metastatic EGFR-mutated advanced NSCLC was successfully used, in ADAURA study, in adjuvant setting vs placebo (planned treatment duration three years), in resected NSCLC patients, stage IB-IIIA. Patients might had adjuvant chemotherapy also, and there was no outcome differences between these two groups. Overall, there was a 79% reduction in the risk of disease recurrence or death (DFS HR was 0.21, p<0.0001). Lorlatinib is the third generation of ALKinhibitors in the treatment of advanced NSCLC. The results of CROWN study where lorlatinib was given in the first line treatment were presented at ESMO 2020. In this randomized study, comparing lorlatinib with crizotinib, lorlatinib was superior in the term of PFS, HR was 0.28, p<0.001, this superiority was particularly pronounced in intracranial disease, where the percent of intracranial response was 82% in lorlatinib arm and only 23% in crizotinib arm, and percent of complete response per CT was 71% vs 7%. Lorlatinib has been recently approved for patients with advanced ALK-positive NSCLC, irrespectively of treatment line. Also of interest were two studies that inovatively used immunologic drugs as a combination in advanced NSCLC: in Check Mate 9LA randomized study, cytotoxic chemotherapy was given in paralell with nivolumab + ipilimumab for first two cycles, and compared with four cycles of chemoherapy. Median OS was significantly better: 15.6 vs 10.9 months, HR 0.66 and a overall response rate was 38% vs 25%. CITYSCAPE study give us inovative combination of two immuno-oncology drugs, tiragolumab as TIGIT inhibitor, and standard atezolizumab. Median PFS was particularly longer in the population of patients with high PD-L1 expression (NE vs 4.11 months, HR 0.30). In gastrointestinal oncology, last year will be remembered by introducing immunotherapy in first line treatment of metastatic colorectal cancer for patients with MSI-H tumors. In KN177, such patients were randomized to receive pembrolizumab or standard chemotherapy+/-biologic therapy, and after second interim analysis, there was a ery clear adventage for pembrolizumab in terms of mPFS (16.5 vs 8.2 months) and duraton of response (at 24 months, 83% vs 35%). The results are impressive, and it is for expected to be confirmed by OS adventage in future analyses. In urological oncology, JAVELIN Bladder 100 study demonstrated that the maintenance avelumab + best supportive care is superior over best supportive care alone after platinum-based first-line chemotherapy in advanced urothelial carcinoma. In overall population, OS was 21.4 vs 14.3 months, HR 0.69, p<0.001, and the results are even better in PD-L1 positive population, with HR 0.56. These results are very probably practice changing, since cytotoxic chemotherapy have very modest achievements in the field of urothelial cancer.
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INTRODUCTION: Osimertinib is a molecular targeted antineoplastic tyrosine kinase inhibitor that is primarily used in the treatment of non-small cell lung cancer (NSCLC). It has been associated with the development of interstitial lung disease/pneumonitis that requires discontinuation of the drug and occurs usually within the first 2-3 months of therapy. Approximately 3% of patients treated with osimertinib will experience lung toxicity. Acute fibrinous and organizing pneumonia (AFOP) is a rare form of interstitial pneumonitis that has been associated with drug toxicity but to our knowledge has not yet been described in association with osimertinib. Here we present one such case. DESCRIPTION: A 77 year old woman with a history of EGFR+ stage IIB adenocarcinoma presented with two weeks of shortness of breath, fevers, and dry cough. She had been started on osimertinib two months prior to presentation. On admission she was noted to be hypoxic with new oxygen requirement of 4L nasal cannula. CT chest showed bilateral ground glass opacities. She was started on empiric vancomycin and zosyn without improvement in symptoms. She underwent bronchoscopy on hospital day 3 with lung biopsy pathology showing AFOP. Infectious workup including bronchoalveolar lavage, blood, and sputum cultures, as well as respiratory viral panel and COVID-19 test was negative. Transthoracic echocardiogram showed normal cardiac function with an ejection fraction of 64%. Given these findings she was started on methylprednisolone 1 mg/kg for TKI-induced pneumonitis on day 5. Her oxygen requirements increased during hospitalization and on day 7 she acutely desaturated and was intubated. Repeat chest CT was negative for pulmonary embolism but showed interval worsening of infiltrates and consolidation at lung bases. Her methylprednisolone was increased to 2 mg/kg on day 10. Her pulmonary function improved and she was extubated to nasal cannula on day 12. DISCUSSION: Molecular targeted antineoplastic agents have been associated with lung toxicity, which can be severe and even fatal. To our knowledge this is the first known case of osimertinib-induced AFOP, which improved with discontinuation of the drug and initiation of high-dose methylprednisolone.
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Introduction: Coronavirus disease 2019 (COVID-19) adversely affects patients with cancer, underscoring the critical need for vaccination. However, the safety of COVID-19 vaccines in patients with solid tumors receiving systemic therapy is inadequately studied. Research Question or Hypothesis: Are COVID-19 vaccines safe in patients with solid tumors receiving systemic therapy? Study Design: Retrospective review of electronic medical records. Methods: Recipients of COVID-19 vaccines between January 1, 2021 and April 30, 2021, while on systemic therapy for solid tumors, were identified. Data were collected from the electronic clinic notes, and adverse events (AEs) were graded according to Common Terminology Criteria for Adverse Events, version 5.0. Results: The analysis included 185 patients;the median age was 71 years, and 55% were female. The most common chemotherapy, immunotherapy, and targeted therapy administered were Oxaliplatin (9%) and taxane-based (13.5%) regimens, anti-programmed death 1 agents (17%), and Osimertinib (3%), respectively. Patients received the following vaccines: BNT162b2 from Pfizer (96/185, 52%), mRNA-1273 from Moderna (79/185, 43%), and JNJ-78436735 from Johnson & Johnson (10/185, 5%). At least one AE was observed in 35 patients (19%);the total number of AEs was 56: 48 grade 1 (86%) and 8 grade 2 (14%). Most adverse events occurred after the second dose (33, 59%). The most frequent grade 1 AEs included injection site pain (7,14.6%), fever (7,14.6%), fatigue (7,14.6%), chills (5,10.4%). The most frequent grade 2 AE was fatigue (3, 37.5%). Therapy was delayed because of AEs in 3 patients (1.6%). The following table summarizes the data: Conclusion: COVID-19 vaccines caused infrequent and mild AEs in patients with solid tumors receiving systemic therapies.