Dabrafenib-trametinib in BRAF V600-mutated non-small-cell lung cancer: a single center real world experience.

Aim: We retrospectively evaluated the effect of dabrafenib/trametinib combination in patients with BRAF-mutated non-small-cell lung cancer (NSCLC) treated in a single center from 2017 to 2022. Patients: The response and safety data of 42 patients (27 treated in first-line and 15 as second/subsequent lines) were analyzed. Results: The objective response was 73.8%, with no differences between patients undergoing first- or second-line. A longer, statistically significant median progression-free survival (PFS) was observed in patients receiving the combination in first-line vs those in the second/subsequent lines (19.9 months [95% CI: 19.7-20] vs 13.1 months [95% CI: 8.6-17.6], respectively; p = 0.012). The median overall survival (OS) was 29.9 months (95% CI: 14.1-45.7) for patients treated with the combination in first-line and 22.4 months (95% CI: 14.6-30.2) for those treated in subsequent lines. The combination was well tolerated. Conclusion: We confirm the efficacy of dabrafenib/trametinib in BRAF-V600-mutated NSCLC.

[Box: see text].

Nanopore sequencing from liquid biopsy: analysis of copy number variations from cell-free DNA of lung cancer patients.

In the "precision oncology" era the characterization of tumor genetic features is a pivotal step in cancer patients' management. Liquid biopsy approaches, such as analysis of cell-free DNA from plasma, represent a powerful and noninvasive strategy to obtain information about the genomic status of the tumor. Sequencing-based analyses of cell-free DNA, currently performed with second generation sequencers, are extremely powerful but poorly scalable and not always accessible also due to instrumentation costs. Third generation sequencing platforms, such as Nanopore sequencers, aim at overcoming these obstacles but, unfortunately, are not designed for cell-free DNA analysis.Here we present a customized workflow to exploit low-coverage Nanopore sequencing for the detection of copy number variations from plasma of cancer patients. Whole genome molecular karyotypes of 6 lung cancer patients and 4 healthy subjects were successfully produced with as few as 2 million reads, and common lung-related copy number alterations were readily detected.This is the first successful use of Nanopore sequencing for copy number profiling from plasma DNA. In this context, Nanopore represents a reliable alternative to Illumina sequencing, with the advantages of minute instrumentation costs and extremely short analysis time.The availability of protocols for Nanopore-based cell-free DNA analysis will make this analysis finally accessible, exploiting the full potential of liquid biopsy both for research and clinical purposes.

A multiparametric approach to improve the prediction of response to immunotherapy in patients with metastatic NSCLC.

BACKGROUND: It is still unclear how to combine biomarkers to identify patients who will truly benefit from anti-PD-1 agents in NSCLC. This study investigates exosomal mRNA expression of PD-L1 and IFN-γ, PD-L1 polymorphisms, tumor mutational load (TML) in circulating cell-free DNA (cfDNA) and radiomic features as possible predictive markers of response to nivolumab and pembrolizumab in metastatic NSCLC patients. METHODS: Patients were enrolled and blood (12 ml) was collected at baseline before receiving anti-PD-1 therapy. Exosome-derived mRNA and cfDNA were extracted to analyse PD-L1 and IFN-γ expression and tumor mutational load (TML) by digital droplet PCR (ddPCR) and next-generation sequencing (NGS), respectively. The PD-L1 single nucleotide polymorphisms (SNPs) c.-14-368 T > C and c.*395G > C, were analysed on genomic DNA by Real-Time PCR. A radiomic analysis was performed on the QUIBIM Precision® V3.0 platform. RESULTS: Thirty-eight patients were enrolled. High baseline IFN-γ was independently associated with shorter median PFS (5.6 months vs. not reached p = 0.0057), and levels of PD-L1 showed an increase at 3 months vs. baseline in patients who progressed (p = 0.01). PD-L1 baseline levels showed significant direct and inverse relationships with radiomic features. Radiomic features also inversely correlated with PD-L1 expression in tumor tissue. In subjects receiving nivolumab, median PFS was shorter in carriers of c.*395GG vs. c.*395GC/CC genotype (2.3 months vs. not reached, p = 0.041). Lastly, responders had higher non-synonymous mutations and more links between co-occurring genetic somatic mutations and ARID1A alterations as well. CONCLUSIONS: A combined multiparametric approach may provide a better understanding of the molecular determinants of response to immunotherapy.

Combining liquid biopsy and radiomics for personalized treatment of lung cancer patients. State of the art and new perspectives.

Lung cancer has become a paradigm for precision medicine in oncology, and liquid biopsy (LB) together with radiomics may have a great potential in this scenario. They are both minimally invasive, easy to perform, and can be repeated during patient's follow-up. Also, increasing evidence suggest that LB and radiomics may provide an efficient way to screen and diagnose tumors at an early stage, including the monitoring of any change in the tumor molecular profile. This could allow treatment optimization, improvement of patients' quality of life, and healthcare-related costs reduction. Latest reports on lung cancer patients suggest a combination of these two strategies, along with cutting-edge data analysis, to decode valuable information regarding tumor type, aggressiveness, progression, and response to treatment. The approach seems more compatible with clinical practice than the current standard, and provides new diagnostic companions being able to suggest the best treatment strategy compared to conventional methods. To implement radiomics and liquid biopsy directly into clinical practice, an artificial intelligence (AI)-based system could help to link patients' clinical data together with tumor molecular profiles and imaging characteristics. AI could also solve problems and limitations related to LB and radiomics methodologies. Further work is needed, including new health policies and the access to large amounts of high-quality and well-organized data, allowing a complementary and synergistic combination of LB and imaging, to provide an attractive choice e in the personalized treatment of lung cancer.

The increase in activating EGFR mutation in plasma is an early biomarker to monitor response to osimertinib: a case report.

BACKGROUND: Systemic treatment of advanced non-small cell lung cancer (NSCLC) has changed dramatically since the introduction of targeted therapies. The analysis of circulating tumor DNA (ctDNA) is a valuable approach to monitor the clonal evolution of tumors during treatment with EGFR-tyrosine kinase inhibitors (TKIs) and to detect resistance mutations. CASE PRESENTATION: A NSCLC patient with exon 19 deletion (ex19del) of EGFR was treated with osimertinib after multiple lines of treatment and obtained a partial response that lasted over 26 months. Blood was collected at each visit and ctDNA was extracted to monitor ex19del by digital droplet PCR. Within a few weeks from the beginning of osimertinib, ex19del disappeared from plasma but appeared again and steadily increased a few months later anticipating tumor progression. Interestingly, the change in ex19del was much more pronounced than other mutations, since T790M appeared 3 months after the increase of ex19del, and C797S was detectable a few weeks before clinical disease progression. Then the patient received cytotoxic chemotherapy, which was associated with a decrease in ex19del and disappearance of T790M and C797S; however, at disease progression, all EGFR mutations increased again in plasma together with MET amplification which was detected by NGS. CONCLUSIONS: The measurement of ex19del changes in ctDNA is a simple and sensitive approach to monitor clinical outcome to osimertinib and, potentially, to other therapeutic interventions.

Understanding the Mechanisms of Resistance in EGFR-Positive NSCLC: From Tissue to Liquid Biopsy to Guide Treatment Strategy.

Liquid biopsy has emerged as an alternative source of nucleic acids for the management of Epidermal Growth Factor Receptor (EGFR)-mutant non-Small Cell Lung Cancer (NSCLC). The use of circulating cell-free DNA (cfDNA) has been recently introduced in clinical practice, resulting in the improvement of the identification of druggable EGFR mutations for the diagnosis and monitoring of response to targeted therapy. EGFR-dependent (T790M and C797S mutations) and independent (Mesenchymal Epithelial Transition [MET] gene amplification, Kirsten Rat Sarcoma [KRAS], Phosphatidyl-Inositol 4,5-bisphosphate 3-Kinase Catalytic subunit Alpha isoform [PI3KCA], and RAF murine sarcoma viral oncogene homolog B1 [BRAF] gene mutations) mechanisms of resistance to EGFR tyrosine kinase inhibitors (TKIs) have been evaluated in plasma samples from NSCLC patients using highly sensitive methods (i.e., digital droplet PCR, Next Generation Sequencing), allowing for the switch to other therapies. Therefore, liquid biopsy is a non-invasive method able to detect the molecular dynamic changes that occur under the pressure of treatment, and to capture tumor heterogeneity more efficiently than is allowed by tissue biopsy. This review addresses how liquid biopsy may be used to guide the choice of treatment strategy in EGFR-mutant NSCLC.

The amount of activating EGFR mutations in circulating cell-free DNA is a marker to monitor osimertinib response.

BACKGROUND: Circulating cell-free DNA (cfDNA) may help understand the molecular response to pharmacologic treatment and provide information on dynamics of clonal heterogeneity. Therefore, this study evaluated the correlation between treatment outcome and activating EGFR mutations (act-EGFR) and T790M in cfDNA in patients with advanced NSCLC given osimertinib. METHODS: Thirty-four NSCLC patients resistant to first/second-generation EGFR-TKIs, positive for both act-EGFR and T790M in cfDNA at the time of progression were enrolled in this study. Plasma samples were obtained at osimertinib baseline and after 3 months of therapy; cfDNA was analyzed by droplet digital PCR and results were expressed as mutant allele frequency (MAF). RESULTS: At baseline, act-EGFR MAF was significantly higher than T790M (p < 0.0001). act-EGFR MAF and T790M/act-EGFR MAF ratio were significantly correlated with disease response (p = 0.02). Cut-off values of act-EGFR MAF and T790M/act-EGFR ratio of 2.6% and 0.22 were found, respectively. The PFS of patients with act-EGFR MAF of > 2.6% and < 2.6%, were 10 months vs. not reached, respectively (p = 0.03), whereas patients with T790M/act-EGFR ≤ 0.22 had poorer PFS than patients with a value of > 0.22 (6 months vs. not reached, respectively, p = 0.01). CONCLUSION: act-EGFR MAF and T790M/act-EGFR MAF ratio are potential markers of outcome in patients treated with osimertinib.

PD-L1 mRNA expression in plasma-derived exosomes is associated with response to anti-PD-1 antibodies in melanoma and NSCLC.

This corrects the article DOI: 10.1038/bjc.2017.85.

Third-Line Chemotherapy with Irinotecan plus 5-Fluorouracil in Caucasian Metastatic Gastric Cancer Patients.

PURPOSE: The aim of this study was to evaluate the activity of the combination of 5-fluorouracil/folinic acid and irinotecan (FOLFIRI) as third-line chemotherapy (CT) in metastatic gastric cancer (mGC) patients pretreated with platinum derivatives, fluoropyrimidines, and taxanes. METHODS: We prospectively collected data of mGC patients treated with third-line FOLFIRI at our institution from 2009 to 2014. Eligible patients should be treated with a fluoropyrimidine-platinum first-line CT and a subsequent taxane-based second-line CT. FOLFIRI consisted of irinotecan 180 mg/m2 and leucovorin 200 mg/m2, followed by 5-fluorouracil 2,800 mg/m2 (administered as 48-hour i.v. continuous infusion from day 1 to 3), with cycles repeated every 2 weeks. Response rate (RR) was evaluated according to RECIST version 1.0, while progression-free (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. RESULTS: A total of 33 patients were included. The majority (97%) had good performance status (0-1 according to ECOG), while median PFS after first-line and second-line CT was 5.2 and 4.4 months, respectively. Two patients experienced an objective response (RR: 6%), while 14 patients achieved disease stabilization (disease control rate: 42%). Median PFS and OS from the start of third-line CT were 3.3 and 7.5 months, respectively. Hematological and nonhematological grade 3-4 toxicities were uncommon and included neutropenia (6.1%), diarrhea (9.1%), vomiting (3%), and asthenia (3%). Febrile neutropenia was not reported. CONCLUSIONS: Third-line CT with FOLFIRI may be an option in heavily pretreated mGC patients with preserved performance status and organ function. This regimen has a favorable safety profile, and signs of activity have been observed after standard first- and second-line CT.

Cardiovascular Toxicity of Antineoplastic Treatments in Hematological Diseases: Focus on Molecular Mechanisms to Improve Therapeutic Management.

In recent years, advancements in the treatment of hematologic neoplasms have led to more effective and less toxic therapeutic schemes, resulting in prolonged patient life expectancy. However, the success of these treatments has also brought about an increased prevalence of cardiovascular adverse events, becoming a significant concern for the growing population of cancer survivors. Antineoplastic therapies, targeting both tumor and organ vessels, contribute to vascular toxicity, influenced by genetic factors and pre-existing vascular diseases. Chemotherapeutic agents and targeted treatments can induce cardiovascular toxicity by affecting endothelial cells and cardiomyocytes through various mechanisms, including hypoxia, vasculature abnormalities, and direct effects on cardiomyocytes. Cardiovascular adverse events encompass a wide range, from cardiac dysfunction to an elevated risk of arrhythmias. While early cardiac events are well-described in clinical trials, delayed toxicities are gaining relevance due to prolonged patient survival. The review focuses on the cardiac and vascular toxicity of antineoplastic drugs in hematological disorders, providing insights into the molecular physiopathology of cancer therapy-associated cardiotoxicity. Understanding how these drugs interact with the heart and blood vessels is essential for predicting, detecting, and managing chemotherapy-related heart issues.

Hypoxia Promotes the Stemness of Mesangiogenic Progenitor Cells and Prevents Osteogenic but not Angiogenic Differentiation.

The stem cell niche in the bone marrow is a hypoxic environment, where the low oxygen tension preserves the pluripotency of stem cells. We have identified mesangiogenic progenitor cells (MPC) exhibiting angiogenic and mesenchymal differentiation capabilities in vitro. The effect of hypoxia on MPC has not been previously explored. In this study, MPCs were isolated from volunteers' bone marrow and cultured under both normoxic and hypoxic conditions (3% O2). MPCs maintained their characteristic morphology and surface marker expression (CD18 + CD31 + CD90-CD73-) under hypoxia. However, hypoxic conditions led to reduced MPC proliferation in primary cultures and hindered their differentiation into mesenchymal stem cells (MSCs) upon exposure to differentiative medium. First passage MSCs derived from MPC appeared unaffected by hypoxia, exhibiting no discernible differences in proliferative potential or cell cycle. However, hypoxia impeded the subsequent osteogenic differentiation of MSCs, as evidenced by decreased hydroxyapatite deposition. Conversely, hypoxia did not impact the angiogenic differentiation potential of MPCs, as demonstrated by spheroid-based assays revealing comparable angiogenic sprouting and tube-like formation capabilities under both hypoxic and normoxic conditions. These findings indicate that hypoxia preserves the stemness phenotype of MPCs, inhibits their differentiation into MSCs, and hampers their osteogenic maturation while leaving their angiogenic potential unaffected. Our study sheds light on the intricate effects of hypoxia on bone marrow-derived MPCs and their differentiation pathways.

Clinical evidence and adverse event management update of patients with RET- rearranged advanced non-small-cell lung cancer (NSCLC) treated with pralsetinib.

Current non-small cell lung cancer (NSCLC) management relies on genome-driven precision oncology thus shifting treatment paradigm towards biomarker-guided tumor-agnostic approaches. Recently, rearranged during transfection (RET) has been endorsed as tissue-agnostic target with sensitivity to RET inhibition. There are currently two selective RET tyrosine kinase inhibitors, pralsetinib and selpercatinib. The recent introduction of pralsetinib in the treatment algorithm of RET-rearranged tumor along with the mounting clinical evidence of pralsetinib durable activity from both randomized and observational studies holds the potential to disclose new avenues in the management of RET fusion positive NSCLC patients. Our narrative review aims to discuss the available clinical evidence on pralsetinib efficacy, particularly on brain metastases, and tolerability profile. In addition, our work explores the relevance of detecting RET fusions upfront in the disease history of patients with NSCLC.

Clinical utility of Next Generation Sequencing of plasma cell-free DNA for the molecular profiling of patients with NSCLC at diagnosis and disease progression.

BACKGROUND: The present study evaluates the utility of NGS analysis of circulating free DNA (cfDNA), which incorporates small amounts of tumor DNA (ctDNA), at diagnosis or at disease progression (PD) in NSCLC patients. METHODS: Comprehensive genomic profiling on cfDNA by NGS were performed in NSCLC patients at diagnosis (if tissue was unavailable/insufficient) or at PD to investigate potential druggable molecular aberrations. Blood samples were collected as routinary diagnostic procedures, DNA was extracted, and the NextSeq 550 Illumina platform was used to run the Roche Avenio ctDNA Expanded Kit for molecular analyses. Gene variants were classified accordingly to the ESCAT score. RESULTS: A total of 106 patients were included in this study; 44 % of cases were requested because of tissue unavailability at the diagnosis and 56 % were requested at the PD. At least one driver alteration was observed in 62 % of cases at diagnosis. Driver druggable variants classified as ESCAT level I were detected in 34 % of patients, including ALK-EML4, ROS1-CD74, EGFR, BRAF, KRAS p.G12C, PI3KCA. In the PD group, most patients were EGFR-positive, progressing to a first line-therapy. Sixty-three percent of patients had at least one driver alteration detected in blood and 17 % of patients had a known biological mechanism of resistance allowing further therapeutic decisions. CONCLUSIONS: The present study confirms the potential of liquid biopsy to detect tumour molecular heterogeneity in NSCLC patients at the diagnosis and at PD, demonstrating that a significant number of druggable mutations and mechanisms of resistance can be detected by NGS analysis on ctDNA.

Mesenchymal Stem Cell in Pancreatic Islet Transplantation.

Pancreatic islet transplantation is a therapeutic option for achieving physiologic regulation of plasma glucose in Type 1 diabetic patients. At the same time, mesenchymal stem cells (MSCs) have demonstrated their potential in controlling graft rejection, the most fearsome complication in organ/tissue transplantation. MSCs can interact with innate and adaptive immune system cells either through direct cell-cell contact or through their secretome including exosomes. In this review, we discuss current findings regarding the graft microenvironment of pancreatic islet recipient patients and the crucial role of MSCs operation as cell managers able to control the immune system to prevent rejection and promote endogenous repair. We also discuss how challenging stressors, such as oxidative stress and impaired vasculogenesis, may jeopardize graft outcomes. In order to face these adverse conditions, we consider either hypoxia-exposure preconditioning of MSCs or human stem cells with angiogenic potential in organoids to overcome islets' lack of vasculature. Along with the shepherding of carbon nanotubes-loaded MSCs to the transplantation site by a magnetic field, these studies look forward to exploiting MSCs stemness and their immunomodulatory properties in pancreatic islet transplantation.

Molecular and Functional Key Features and Oncogenic Drivers in Thymic Carcinomas.

Thymic epithelial tumors, comprising thymic carcinomas and thymomas, are rare neoplasms. They differ in histology, prognosis, and association with autoimmune diseases such as myasthenia gravis. Thymomas, but not thymic carcinomas, often harbor GTF2I mutations. Mutations of CDKN2A, TP53, and CDKN2B are the most common thymic carcinomas. The acquisition of mutations in genes that control chromatin modifications and epigenetic regulation occurs in the advanced stages of thymic carcinomas. Anti-angiogenic drugs and immune checkpoint inhibitors targeting the PD-1/PD-L1 axis have shown promising results for the treatment of unresectable tumors. Since thymic carcinomas are frankly aggressive tumors, this report presents insights into their oncogenic drivers, categorized under the established hallmarks of cancer.

Gene-network analysis predicts clinical response to immunotherapy in patients affected by NSCLC.

OBJECTIVES: Predictive biomarkers of response to immune checkpoint inhibitors (ICIs) have been extensively studied in non-small cell lung cancer (NSCLC) with controversial results. Recently, gene-network analysis emerged as a new tool to address tumor biology and behavior, representing a potential tool to evaluate response to therapies. METHODS: Clinical data and genetic profiles of 644 advanced NSCLCs were retrieved from cBioPortal and the Cancer Genome Atlas (TCGA); 243 ICI-treated NSCLCs were used to identify an immunotherapy response signatures via mutated gene network analysis and K-means unsupervised clustering. Signatures predictive values were tested in an external dataset of 242 cases and assessed versus a control group of 159 NSCLCs treated with standard chemotherapy. RESULTS: At least two mutations in the coding sequence of genes belonging to the chromatin remodelling pathway (A signature), and/or at least two mutations of genes involved in cell-to-cell signalling pathways (B signature), showed positive prediction in ICI-treated advanced NSCLC. Signatures performed best when combined for patients undergoing first-line immunotherapy, and for those receiving combined ICIs. CONCLUSIONS: Alterations in genes related to chromatin remodelling complexes and cell-to-cell crosstalk may force dysfunctional immune evasion, explaining susceptibility to immunotherapy. Therefore, exploring mutated gene networks could be valuable for determining essential biological interactions, contributing to treatment personalization.

Comparison of digital PCR systems for the analysis of liquid biopsy samples of patients affected by lung and colorectal cancer.

BACKGROUND AND AIMS: Highly sensitive technologies are available for the molecular characterization of solid tumors, including digital PCR (dPCR). Liquid biopsy, based on the analysis of cell-free DNA (cfDNA), is often used to assess EGFR or RAS alterations in lung and colorectal cancers. Our study aimed to compare the results of two different dPCR platforms for the detection of mutations in cfDNA. METHODS: Plasma samples from lung and colorectal cancer patients collected as per routine procedures have been tested. cfDNA Was extracted from plasma, and samples were screened on the droplet digital PCR (ddPCR, BioRad) and solid dPCR QIAcuity (Qiagen). RESULTS: A total of 42 samples were analyzed, obtained from 20 Non-Small Cell Lung Cancer (NSCLC) patients carrying an EGFR or a KRAS mutation on tissue at diagnosis, and from 22 samples of colorectal cancer (CRC) patients, 10 of which presenting a KRAS mutation. EGFR mutation detection was 58.8% for ddPCR and 100% for dPCR (κ = 0.54; 95% CI, 0.37-0.71), compared to tissue results. The detection rate for RAS mutations was 72.7% for ddPCR and 86.4% for dPCR (κ = 0.34; 95% CI, 0.01-0.68), compared to tissue results. CONCLUSIONS: This study showed moderate agreement between dPCR and ddPCR. Sampling effect or threshold settings may potentially explain the differences in the cfDNA data between the two different platforms.

Somatic mutations of thymic epithelial tumors with myasthenia gravis.

Background: Thymic epithelial tumors are rare malignant neoplasms that are frequently associated with paraneoplastic syndromes, especially myasthenia gravis. GTF2I is an oncogene mutated in a subgroup of thymomas that is reputed to drive their growth. However, for GTF2I wild-type tumors, the relevant mutations remain to be identified. Methods: We performed a meta-analysis and identified 4,208 mutations in 339 patients. We defined a panel of 63 genes frequently mutated in thymic epithelial tumors, which we used to design a custom assay for next-generation sequencing. We sequenced tumor DNA from 67 thymomas of patients with myasthenia gravis who underwent resection in our institution. Results: Among the 67 thymomas, there were 238 mutations, 83 of which were in coding sequences. There were 14 GTF2I mutations in 6 A, 5 AB, 2 B2 thymomas, and one in a thymoma with unspecified histology. No other oncogenes showed recurrent mutations, while sixteen tumor suppressor genes were predicted to be inactivated. Even with a dedicated assay for the identification of specific somatic mutations in thymic epithelial tumors, only GTF2I mutations were found to be significantly recurrent. Conclusion: Our evaluation provides insights into the mutational landscape of thymic epithelial tumors, identifies recurrent mutations in different histotypes, and describes the design and implementation of a custom panel for targeted resequencing. These findings contribute to a better understanding of the genetic basis of thymic epithelial tumors and may have implications for future research and treatment strategies.

STYLE (NCT03449173): A Phase 2 Trial of Sunitinib in Patients With Type B3 Thymoma or Thymic Carcinoma in Second and Further Lines.

INTRODUCTION: Thymic malignancies are rare tumors with few therapeutic options. The STYLE trial was aimed to evaluate activity and safety of sunitinib in advanced or recurrent type B3 thymoma (T) and thymic carcinoma (TC). METHODS: In this multicenter, Simon 2 stages, phase 2 trial, patients with pretreated T or TC were enrolled in two cohorts and assessed separately. Sunitinib was administered 50 mg daily for 4 weeks, followed by a 2-week rest period (schedule 4/2), until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Progression-free survival, overall survival, disease control rate and safety were secondary endpoints. RESULTS: From March 2017 to January 2022, 12 patients with T and 32 patients with TC were enrolled. At stage 1, ORR was 0% (90% confidence interval [CI]: 0.0-22.1) in T and 16.7% (90% CI: 3.1-43.8) in TC, so the T cohort was closed. At stage 2, the primary endpoint was met for TC with ORR of 21.7% (90% CI: 9.0%-40.4%). In the intention-to-treat analysis, disease control rate was 91.7% (95% CI: 61.5%-99.8%) in Ts and 89.3% (95% CI: 71.8%-97.7%) in TCs. Median progression-free survival was 7.7 months (95% CI: 2.4-45.5) in Ts and 8.8 months (95% CI: 5.3-11.1) in TCs; median overall survival was 47.9 months (95% CI: 4.5-not reached) in Ts and 27.8 months (95% CI: 13.2-53.2) in TCs. Adverse events occurred in 91.7% Ts and 93.5% TCs. Grade 3 or greater treatment-related adverse events were reported in 25.0% Ts and 51.6% TCs. CONCLUSIONS: This trial confirms the activity of sunitinib in patients with TC, supporting its use as a second-line treatment, albeit with potential toxicity that requires dose adjustment.

Amivantamab in the Treatment of Metastatic NSCLC: Patient Selection and Special Considerations.

Amivantamab is a bispecific antibody that recognizes epidermal growth factor receptor (EGFR) and MET proto-oncogene (MET). In May 2021, the Food and Drug Administration gave an accelerated approval of amivantamab for the treatment of non-small cell lung cancer (NSCLC) patients with EGFR exon 20 insertions (Exon20ins) who progressed after platinum-based chemotherapy. Amivantamab prevents ligand binding to EGFR and MET and the dimerization of the receptors suppressing the downstream signal transduction. Moreover, amivantamab determines antibody dependent cellular cytotoxicity and down regulation of cell surface proteins through internalization of the receptor and trogocytosis. Preliminary results of the Phase I/IB CHRYSALIS trial demonstrated an objective response rate of 40% with a median duration of response of 11.1 months (95% CI 9.6-not reached) in 81 patients treated with amivantamab with pretreated NSCLC with Exon20ins EGFR mutations. In a different cohort of the CHRYSALIS trial, patients with Ex19del and L858R EGFR mutations were enrolled after progression on osimertinib. 121 and 45 patients received amivantamab or a combination with lazertinib, a third-generation tyrosine kinase inhibitor, respectively. The objective response rate was 19% and 36% in patients treated with amivantamab alone or in combination with lazertinib, with a median progression-free survival of 6.9 (95% CI: 3.2-5.3) and 11.1 (95% CI: 3.7-9.5) months, respectively. All 20 patients with Ex19del and L858R EGFR mutations who received amivantamab and lazertinib as their first line treatment achieved an objective response. Amivantamab is currently under evaluation in Phase III clinical trials for the first line treatment of NSCLCs with Exon20ins EGFR mutations in combination with chemotherapy (PAPILLON), for the first line therapy of Ex19del and L858R mutated NSCLCs in combination with lazertinib (MARIPOSA) and in combination with chemotherapy and lazertinib in NSCLCs who progressed on osimertinib (MARIPOSA-2).