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Key Points Heat shock protein 90 (HSP90) is a molecular chaperone of numerous oncoproteins. Therefore, cancer cells can be considered to be 'addicted' to this molecule. HSP90 is also a mediator of cellular homeostasis. As such, it facilitates numerous transient low-affinity protein–protein interactions that have only recently been identified using bioinformatic and proteomic techniques. Although primarily a cytoplasmic protein, HSP90 affects diverse nuclear processes, including transcription, chromatin remodelling and DNA damage-induced mutation. HSP90 is a conformationally dynamic protein. ATP binding to the amino (N) domain and its subsequent hydrolysis by HSP90 drive a conformational cycle that is essential for chaperone activity. In eukaryotes, co-chaperones and post-translational modifications regulate both client interactions with HSP90 and HSP90 ATPase activity. Co-chaperones and post-translational modifications can also affect the efficacy of HSP90 inhibitors. HSP90 inhibitors currently under clinical evaluation interact with the N domain ATP-binding pocket, prevent ATP binding, and stop the chaperone cycle, leading to client protein degradation. Because of the HSP90 client repertoire, HSP90 inhibitors may combat oncogene switching, which is an important mechanism of tumour escape from tyrosine kinase inhibitors. Derivatives of the coumarin antibiotic novobiocin represent an alternative strategy for inhibiting HSP90 by targeting a unique carboxy-terminal (C) domain. Optimal development of HSP90-directed therapeutics will depend on synthesizing information gained from careful genetic analysis of primary and metastatic tumours with an understanding of the unique environmental context in which the tumour is thriving at the expense of the host. Numerous oncoproteins depend on the molecular chaperone heat shock protein 90 (HSP90). However, the optimal use of HSP90-targeted therapeutics will depend on understanding the complexity of HSP90 regulation and the degree to which the chaperone participates in both neoplastic and normal cellular physiology. The molecular chaperone heat shock protein 90 (HSP90) has been used by cancer cells to facilitate the function of numerous oncoproteins, and it can be argued that cancer cells are 'addicted' to HSP90. However, although recent reports of the early clinical efficacy of HSP90 inhibitors are encouraging, the optimal use of HSP90-targeted therapeutics will depend on understanding the complexity of HSP90 regulation and the degree to which HSP90 participates in both neoplastic and normal cellular physiology.

Among patients with lung cancer that expressed programmed death ligand 1, the anti–PD-L1 antibody atezolizumab was compared with chemotherapy in a randomized trial. In the subgroup with the highest PD-L1 expression, the median overall survival was 20.2 months with atezolizumab and 13.1 months with chemotherapy.

Nonalcoholic fatty liver disease (NAFLD) and its evolution to inflammatory steatohepatitis (NASH) are the most common causes of chronic liver damage and transplantation that are reaching epidemic proportions due to the upraising incidence of metabolic syndrome, obesity, and diabetes. Currently, there is no approved treatment for NASH. The mitochondrial citrate carrier, Slc25a1, has been proposed to play an important role in lipid metabolism, suggesting a potential role for this protein in the pathogenesis of this disease. Here, we show that Slc25a1 inhibition with a specific inhibitor compound, CTPI-2, halts salient alterations of NASH reverting steatosis, preventing the evolution to steatohepatitis, reducing inflammatory macrophage infiltration in the liver and adipose tissue, while starkly mitigating obesity induced by a high-fat diet. These effects are differentially recapitulated by a global ablation of one copy of the Slc25a1 gene or by a liver-targeted Slc25a1 knockout, which unravel dose-dependent and tissue-specific functions of this protein. Mechanistically, through citrate-dependent activities, Slc25a1 inhibition rewires the lipogenic program, blunts signaling from peroxisome proliferator-activated receptor gamma, a key regulator of glucose and lipid metabolism, and inhibits the expression of gluconeogenic genes. The combination of these activities leads not only to inhibition of lipid anabolic processes, but also to a normalization of hyperglycemia and glucose intolerance as well. In summary, our data show for the first time that Slc25a1 serves as an important player in the pathogenesis of fatty liver disease and thus, provides a potentially exploitable and novel therapeutic target.

Key Points Our understanding of non-small-cell lung cancer (NSCLC) has evolved from a single disease entity that was treated with a one-size-fits-all approach to a disease comprising clinically, histologically and genetically diverse subtypes Further subtypes of tumours with EGFR mutations and ALK translocations are now recognized based on the type of resistance mechanism to targeted therapy; these subtypes have important therapeutic implications Whereas several NSCLC subtypes that are responsive to targeted therapies have been identified, at present, no single molecular determinant of response to an immunotherapeutic agent has been identified Although the importance of genotype-driven treatment decisions is recognized, challenges relating to tissue acquisition and processing, biomarker platforms, tumour heterogeneity, and evaluation of molecular markers and drugs pose practical barriers to clinical application of this paradigm With further development of targeted therapies and immunotherapies, clinicians will probably face the daunting task of elucidating the ideal timing and sequence of molecularly targeted therapy, immunotherapy, and chemotherapy Despite improvements in outcome for select patient subgroups, progress is needed in the adjuvant setting, squamous-cell lung cancers, KRAS -mutated tumours, and tumours with no detectable genetic alterations The recognition of non-small-cell lung cancer (NSCLC) as a heterogeneous disease and ongoing efforts to characterize disease subtypes based on genotype and histology have resulted in dramatic improvements in outcomes for select patient subgroups. However, many challenges remain, not least acquired therapeutic resistance and the related issue of how to best use the available therapies. In this Review, the authors provide an overview of the key developments in NSCLC therapy, describe efforts to tackle therapeutic resistance, and discuss potential strategies to further optimize patient outcomes by stratifying treatments according to particular disease subtypes. In the past decade, the characterization of non-small-cell lung cancer (NSCLC) into subtypes based on genotype and histology has resulted in dramatic improvements in disease outcome in select patient subgroups. In particular, molecularly targeted agents that inhibit EGFR or ALK are approved for the treatment of NSCLC harbouring genetic alterations in the genes encoding these proteins. Although acquired resistance usually limits the duration of response to these therapies, a number of new agents have proven effective at tackling specific resistance mechanisms to first-generation inhibitors. Large initiatives are starting to address the role of biomarker-driven targeted therapy in squamous lung cancers, and in the adjuvant setting. Immunotherapy undeniably holds great promise and our understanding of subsets of NSCLC based on patterns of immune response is continuing to evolve. In addition, efforts are underway to identify rare genomic subsets through genomic screening, functional studies, and molecular characterization of exceptional responders. This Review provides an overview of the key developments in the treatment of NSCLC, and discusses potential strategies to further optimize therapy by targeting disease subtypes.

Systemic treatment of advanced non-small cell lung cancer (NSCLC) has undergone remarkable changes in the last decade, with the introduction of targeted therapies and immunotherapy. The identification of activating mutations in the epidermal growth factor receptor (EGFR) gene (deletions in exon 19 [Del19] and point mutation L858R in exon 21) has been the first important step toward molecularly guided precision therapy in lung cancer. Several randomized trials comparing EGFR tyrosine kinase inhibitors (TKIs) (gefitinib, erlotinib, and afatinib) to standard chemotherapy in first-line treatment of advanced EGFR-mutant NSCLC showed significant improvement in progression-free survival (PFS) and in response rate, with lower rates of adverse events (AEs) and better symptom control. However, none of these trials showed significant improvement in overall survival (OS). Despite impressive responses with EGFR-TKI, disease invariably progresses after 9 to 13 months, due to acquired resistance. Dacomitinib is a potent, irreversible, highly selective, second-generation EGFR-TKI, which inhibits the signaling from both heterodimers and homodimers of all the members of the human epidermal growth factor receptor (HER) family. Here, we review the clinical development of dacomitinib from phase I to phase III, with particular attention to its toxicity and on its activity on T790M mutation. Then, we critically examine the results of ARCHER 1050, a study that was crucial for Food and Drug Administration (FDA) approval. ARCHER 1050 was the first randomized phase III study comparing dacomitinib with gefitinib, in first-line treatment of patients with advanced EGFR-mutated NSCLC. Dacomitinib was superior to gefitinib in terms of primary end-point (14.7 vs 9.2 months) and OS (34.1 vs 26.8 months). The incidence of diarrhea, skin rash, mucositis and, consequently, dose reductions was higher with dacomitinib, while hepatic toxicity was higher with gefitinib. Dacomitinib constitutes one of the standard first-line options in patients with advanced EGFR-mutated NSCLC.

Treatment options are limited for patients with thymic carcinoma. These aggressive tumours are not typically associated with paraneoplastic autoimmune disorders, and strong PD-L1 expression has been reported in thymic epithelial tumours. We aimed to assess the activity of pembrolizumab, a monoclonal antibody that targets PD-1, in patients with advanced thymic carcinoma. We completed a single-arm phase 2 study of pembrolizumab in patients with recurrent thymic carcinoma who had progressed after at least one line of chemotherapy. This was a single-centre study performed at Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA. Key inclusion criteria were an Eastern Cooperative Oncology Group performance status of 0–2, no history of autoimmune disease or other malignancy requiring treatment or laboratory abnormality, and adequate organ function. Patients received 200 mg of pembrolizumab every 3 weeks for up to 2 years. The primary objective of the study was the proportion of patients who had achieved a response assessed with Response Evaluation Criteria in Solid Tumors version 1.1. Analysis was per protocol, in all eligible patients. The study is registered with ClinicalTrials.gov, number NCT02364076, and is closed to accrual; we report the final analysis. 41 patients were enrolled from March 12, 2015, to Dec 16, 2016, of whom 40 were eligible and evaluable and one was excluded because of elevated liver enzymes at screening. The median follow-up was 20 months (IQR 14–26). The proportion of patients who achieved a response was 22·5% (95% CI 10·8–38·5); one (3%) patient achieved a complete response, eight (20%) patients achieved partial responses, and 21 (53%) patients achieved stable disease. The most common grade 3 or 4 adverse events were increased aspartate aminotransferase and alanine aminotransferase (five [13%] patients each). Six (15%) patients developed severe autoimmune toxicity, including two (5%) patients with myocarditis. There were 17 deaths at the time of analysis, but no deaths due to toxicity. Pembrolizumab is a promising treatment option in patients with thymic carcinoma. Because severe autoimmune disorders are more frequent in thymic carcinoma than in other tumour types, careful monitoring is essential. Merck & Co.

Patients with advanced type B3 thymoma and thymic carcinoma resistant to chemotherapy have few treatment options. We report the efficacy and safety results of the combination of the anti-PD-L1 inhibitor avelumab with the anti-angiogenesis drug axitinib in patients with advanced type B3 thymoma and thymic carcinoma. CAVEATT was a single-arm, multicentre, phase 2 trial, conducted in two Italian centres (the European Instituteof Oncology and the Humanitas Institute, Milan) in patients with histologically confirmed type B3 thymoma or thymic carcinoma, with advanced stage of disease who had progressed after at least one line of platinum-based chemotherapy. Previous treatment with an anti-angiogenesis drug was allowed but not with immune checkpoint inhibitors. Other inclusion criteria were age 18 years or older, an Eastern Cooperative Oncology Group performance status of 0–2, progressive disease, and presence of measurable disease according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1. Patients received avelumab 10 mg/kg intravenously every 2 weeks and axitinib 5 mg orally twice daily until disease progression or unacceptable toxicity. The primary endpoint was the centrally assessed overall response rate according to RECIST version 1.1. Patients who received at least one cycle of treatment and had at least one CT scan after treatment start at scheduled time point by protocol were judged assessable for response and were included in efficacy and safety analyses. This study is registered with EUDRACT, 2017–004048–38; enrolment is completed and follow-up is ongoing. Between April 22, 2019, and June 30, 2021, 32 patients were enrolled. 27 patients had a thymic carcinoma, three a type B3 thymoma, and two a mixed type B3 thymoma and thymic carcinoma. 29 (91%) of 32 patients had stage IVB disease and 13 (41%) of 32 had been pretreated with an anti-angiogenesis drug. 11 of 32 patients had an overall response; thus the overall response rate was 34% (90% CI 21–50); no patients had a complete response, 11 (34%) had a partial response, 18 (56%) had stable disease, and in two patients (6%) progressive disease was the best response. The most common grade 3 or 4 adverse event was hypertension (grade 3 in six [19%] of 32 patients). Four (12%) of 32 patients developed serious adverse events that were new-onset immune-related adverse events, including one grade 3 interstitial pneumonitis, one grade 4 polymyositis, and two grade 3 polymyositis. There were no treatment-related deaths. Avelumab combined with axitinib has promising anti-tumour activity and acceptable toxicity in patients with advanced type B3 thymoma and thymic carcinoma progressing after chemotherapy, and could emerge as a new standard treatment option in this setting. Pfizer.

The pathogenesis of thymic epithelial tumors (TETs) is poorly understood. Recently we reported the frequent occurrence of a missense mutation in the GTF2I gene in TETs and hypothesized that GTF2I mutation might contribute to thymic tumorigenesis. Expression of mutant TFII-I altered the transcriptome of normal thymic epithelial cells and upregulated several oncogenic genes. Gtf2i L424H knockin cells exhibited cell transformation, aneuploidy, and increase tumor growth and survival under glucose deprivation or DNA damage. Gtf2i mutation also increased the expression of several glycolytic enzymes, cyclooxygenase-2, and caused modifications of lipid metabolism. Elevated cyclooxygenase-2 expression by Gtf2i mutation was required for survival under metabolic stress and cellular transformation of thymic epithelial cells. Our findings identify GTF2I mutation as a new oncogenic driver that is responsible for transformation of thymic epithelial cells.

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). Keywords: amivantamab, exon 20 insertion of EGFR, NSCLC

First-line chemotherapy for advanced non-small-cell lung cancer (NSCLC) is usually limited to four to six cycles. Maintenance therapy can delay progression and prolong survival. The oral epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor erlotinib has proven efficacy and tolerability in second-line NSCLC. We designed the phase 3, placebo-controlled Sequential Tarceva in Unresectable NSCLC (SATURN; BO18192) study to assess use of erlotinib as maintenance therapy in patients with non-progressive disease following first-line platinum-doublet chemotherapy. Between December, 2005, and May, 2008, 1949 patients were included in the run-in phase (four cycles of platinum-based chemotherapy). At the end of the run-in phase, 889 patients who did not have progressive disease were entered into the main study, and were randomly allocated using a 1:1 adaptive randomisation method through a third-party interactive voice response system to receive erlotinib (150 mg/day; n=438) or placebo (n=451) until progression or unacceptable toxicity. Patients were stratified by EGFR immunohistochemistry status, stage, Eastern Cooperative Oncology Group performance status, chemotherapy regimen, smoking history, and region. Co-primary endpoints were progression-free survival (PFS) in all analysable patients irrespective of EGFR status, and PFS in patients whose tumours had EGFR protein overexpression, as determined by immunohistochemistry. This study is registered with www.ClinicalTrials.gov, number NCT00556712. 884 patients were analysable for PFS; 437 in the erlotinib group and 447 in the placebo group. After a median follow-up of 11·4 months for the erlotinib group and 11·5 months for the placebo group, median PFS was significantly longer with erlotinib than with placebo: 12·3 weeks for patients in the erlotinib group versus 11·1 weeks for those in the placebo group (HR 0·71, 95% CI 0·62–0·82; p<0·0001). PFS was also significantly longer in patients with EGFR-positive immunohistochemistry who were treated with erlotinib (n=307) compared with EGFR-positive patients given placebo (n=311; median PFS 12·3 weeks in the erlotinib group vs 11·1 weeks in the placebo group; HR 0·69, 0·58–0·82; p<0·0001). The most common grade 3 or higher adverse events were rash (37 [9%] of 443 patients in the erlotinib group vs none of 445 in the placebo group) and diarrhoea (seven [2%] of 443 patients vs none of 445). Serious adverse events were reported in 47 patients (11%) on erlotinib compared with 34 patients (8%) on placebo. The most common serious adverse event was pneumonia (seven cases [2%] with erlotinib and four [<1%] with placebo). Maintenance therapy with erlotinib for patients with NSCLC is well tolerated and significantly prolongs PFS compared with placebo. First-line maintenance with erlotinib could be considered in patients who do not progress after four cycles of chemotherapy. F Hoffmann-La Roche Ltd.