Adjuvant chemotherapy increases overall survival of patients with completely resected non-small cell lung cancer. Adjuvant therapy with immune checkpoint inhibitors and tyrosine kinase inhibitors have further improved outcome in selected patients. These therapeutic achievements are discussed in the present commentary.

PURPOSE OF REVIEW:The purpose of this review is to summarize the breakthroughs in the systemic treatment of patients with nonsmall cell lung cancer (NSCLC) during the last five decades. RECENT FINDINGS:Chemotherapy was established in metastatic, locally advanced and early-stage NSCLC. Tyrosine kinase inhibitors have become standard for palliative and adjuvant therapy in patients with driver mutation-positive NSCLC. Immune checkpoint inhibitors were established in operable, locally advanced and metastatic NSCLC. Antiemetics, hematopoietic growth factors, bisphosphonates and opioids improved palliative care. SUMMARY:Breakthroughs in the systemic therapy of NSCLC during the last five decades included chemotherapy, targeted therapies, immune checkpoint inhibitors and better supportive care.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are the current recommended option for the first-line treatment of patients with EGFR-mutant non-small cell lung cancer (NSCLC). Resistance to first-generation TKIs led to the development of second- and third-generation TKIs with improved clinical outcomes. However, sequential administration of TKIs has led to the emergence of new EGFR resistance mutations and persistent tumor cell survival. This evidence highlights the potential role of EGFR in transducing growth signals in NSCLC tumor cells. Therefore, dual inhibition of EGFR using combinations of anti-EGFR monoclonal antibodies (mAbs) and EGFR-TKIs may offer a unique treatment strategy to suppress tumor cell growth. Several clinical studies have demonstrated the benefits of dual blockade of EGFR using anti-EGFR mAbs coupled with EGFR-TKIs in overcoming treatment resistance in patients with EGFR-mutated NSCLC. However, a single treatment option may not result in the same clinical benefits in all patients with acquired resistance. Biomarkers, including EGFR overexpression, EGFR gene copy number, EGFR and KRAS mutations, and circulating tumor DNA, have been associated with improved clinical efficacy with anti-EGFR mAbs in patients with NSCLC and acquired resistance. Further investigation of biomarkers may allow patient selection for those who could benefit from anti-EGFR mAbs in combination with EGFR-TKIs. This review summarizes findings of recent studies of anti-EGFR mAbs in combination with EGFR-TKIs for the treatment of patients with EGFR-mutated NSCLC, as well as clinical evidence for potential biomarkers towards personalized targeted medicine.

Purpose of reviewThe purpose of the review is to summarize the current status of immune checkpoint inhibitors as adjuvant therapy in patients with resected nonsmall cell lung cancer (NSCLC).Recent findingsThe IMpower010 phase 3 trial demonstrated improved disease-free survival and, in case of PD-L1 at least 50%, also improved overall survival for atezolizumab compared to best supportive care among patients with completely resected stage II-IIIA NSCLC. The PEARLS/KEYNOTE-091 trial showed increased disease-free survival for pembrolizumab among patients with stage IB-IIIA NSCLC. Trials with nivolumab and durvalumab are ongoing.SummaryAtezolizumab or pembrolizumab have become options for adjuvant therapy in patients with completely resected NSCLC.

Promising findings across oncogenic targets S149 Stage I-III disease: surgical and systemic options S151 Immune-based strategies are raising hope in small

aDepartment of Medicine I, Medical University of Vienna, Vienna, Austria bDepartment of Oncology, Shanghai Pulmonary Hospital, Tongji University, Shanghai, China Correspondence to Robert Pirker, MD, Department of Medicine I, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria. E-mail: [email protected]

Abstract Objective We aimed to investigate whether (1) psychological and social indicators influence survival in patients diagnosed with cancer or haematologic malignancies when important biological aspects are controlled for, (2) psychological, social and biological indicators can be utilised to design one collated index for survival, usable in clinical practice to identify patients at risk of shorter survival and to improve personalised healthcare provision. Methods In this cross‐sectional study, 2263 patients with cancer or haematologic malignancies participated. We analysed 15 biological, psychological and social indicators as risk factors for survival with a Cox proportional hazards model. Indicators significantly associated with survival were combined to compute models for the identification of patient groups with different risks of death. The training sample contained 1122 patients. Validation samples included the remaining 1141 patients, the total sample, as well as groups with different cancer entities. Results Five indicators were found to significantly impact survival: Cancer site (HR: 3.56), metastatic disease (HR: 1.88), symptoms of depression (HR: 1.34), female sex (HR: 0.73) and anaemia (HR: 0.48). Combining these indicators to a model, we developed the Cancer Survival Index, identifying three distinct groups of patients with estimated survival times of 47.2 months, 141 months and 198.2 months (p < 0.001). Post hoc analysis of the influence of depression on survival showed a mediating effect of the following four factors, related to both depression and survival: previous psychiatric conditions, employment status, metastatic disease and haemoglobin levels. Conclusions Psychosocial and biological factors impact survival in various malignancies and can be utilised jointly to compute an index for estimating the survival of each patient individually—the Cancer Survival Index.

The current World Health Organization (WHO) Classification of acute myeloid leukemia (AML), developed in 2016 and published in 2017, codifies the defining features of AML and recognizes several subtypes based on clinical, morphologic, and genetic features. This classification is widely used for the purposes of assigning patients to specific therapeutic approaches and entry into clinical trials. Although the WHO Classification ultimately has its origins in the original 1976 French-American-British Classification, it has been periodically updated by the incorporation of a large body of evidence and input from both diagnosticians and clinicians who study and treat AML. Nevertheless, the recent accumulation of genetic data on the molecular underpinnings of myeloid neoplasms as well as numerous recently approved novel therapies have highlighted areas of controversy in how we currently define and classify AML; the 2016 WHO Classification will continually be revised and updated in future versions based on these advances. The purpose of this review is to explore areas of potential refinement in the current WHO Classification of AML, both in terms of its criteria defining the disease as well as the specific disease subtypes.

Purpose of review The purpose of the review is to summarize immunotherapy combinations in advanced nonsmall cell lung cancer (NSCLC). Recent findings First-line platinum-based chemotherapy plus an immune checkpoint inhibitor has improved progression-free and overall survival compared to chemotherapy alone in patients with advanced NSCLC. Although the benefits appear to increase with higher programmed death ligand 1 (PD-L1) expression, patients with low PD-L1 also benefit. Nivolumab plus ipilimumab has also been established as a treatment option. Combinations of immune checkpoint inhibitors with olaparib or lenvatinib are studied within phase 3 trials. Summary Platinum-based doublets combined with an immune checkpoint inhibitor have become standard first-line therapy. Other combinations are under clinical development.

Austria is located in Central Europe and surrounded by Germany and the Czech Republic in the North, Slovakia and Hungary in the East, Slovenia and Italy in the South, and Liechtenstein and Switzerland in the West (Fig. 1). Austria has been a member of the European Union since 1995. Austria has a current population of approximately 8.9 million people and consists of nine Federal Provinces (Fig. 1). Vienna with nearly 2 million inhabitants is the capital city and has regularly been ranked among the most livable cities in the world.

The vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are involved in activation of angiogenesis during tumor progression. Therefore, blockade of VEGF or VEGFR has been studied as a therapeutic strategy in advanced non-small-cell lung cancer (NSCLC) (1). Carboplatin plus paclitaxel combined with bevacizumab has been established as a first-line therapy for patients with advanced non-squamous NSCLC. Docetaxel plus ramucirumab has been established as a second-line treatment for patients with advanced NSCLC. VEGFR tyrosine kinase inhibitors (TKIs) were studied in combination with chemotherapy or as single agents. Docetaxel plus nintedanib has become a second-line treatment for patients with adenocarcinomas. When added to first-line chemotherapy, neither sorafenib nor motesanib improved overall survival of patients. Based on meta-analyses, chemotherapy plus VEGFR TKIs improved response rates and progression-free survival but did not prolong overall survival in patients with advanced NSCLC (2) and was also associated with increased toxicity compared to chemotherapy alone (3). Results of trials with VEGFR TKIs as single agents with focus on phase 3 trials are summarized here. Vandetanib failed to improve overall survival compared to placebo in patients with advanced NSCLC who had been pretreated with an EGFR tyrosine kinase inhibitor and one or two chemotherapy regimens (4). The MISSION phase 3 trial also failed to show a survival benefit for sorafenib compared to placebo in patients with advanced predominantly nonsquamous NSCLC who had been pretreated with two or three treatment regimens (5). The hazard ratio was 0.99 and median survival times were 8.2 and 8.3 months, respectively. Sorafenib improved progression-free survival (hazard ratio 0.61). Among 89 patients with epidermal growth factor receptor mutations, sorafenib improved overall survival (hazard ratio 0.48) and progression-free survival (hazard ratio 0.27). Side effects of sorafenib were rash, diarrhea and fatigue. Sunitinib as maintenance therapy improved progression-free survival but had no impact on survival of patients with advanced NSCLC (6). The phase 3 ALTER 0303 trial evaluated anlotinib compared to placebo in Chinese patients with advanced NSCLC (7). Anlotinib targets VEGFR 1-3, endothelial growth factor receptor, fibroblast growth factor receptor 1-4, platelet-derived growth factor receptor α and β, and stem cell factor receptor. Patients were randomized 2:1 to anlotinib at 12 mg daily (n=296) or placebo (n=143). The primary endpoint was overall survival. Anlotinib improved overall survival compared to placebo. The hazard ratio was 0.68 (95% CI 0.54-0.87; p=0.002) and median survival times were 9.6 and 6.3 months, respectively. Progression-free survival was also increased with anlotinib. The hazard ratio was 0.25 (95% CI 0.19-0.31; p< 0.001) and median progression-free survival times were 5.4 and 1.4 months, respectively. Grade 3 or higher adverse events with anlotinib arm were hypertension and hyponatremia. Other side effects more common with anlotinib were fatigue, anorexia, hand-foot syndrome, hyperlipidemia and thyroid-stimulating hormone elevation. The authors concluded that anlotinib is a potential third-line or further therapy for Chinese patients with advanced NSCLC. Apatinib, an inhibitor of VEGFR-2, has also shown efficacy in patients with advanced NSCLC that failed prior chemotherapy or EGFR-TKIs (8). The multikinase inhibitor lenvatinib is directed against VEGFR 1-3, fibroblast growth factor receptors 1-4, RET and other targets (9). Lenvatinib resulted in a response rate of 16% and a median progression-free survival of 7.3 months among 25 patients with RET fusion-positive lung cancer (10). Lenvatinib has been studied in combination with pembrolizumab in patients with advanced NSCLC. In a phase 1b/2 trial, pembrolizumab plus lenvatinib resulted in a response rate of 33% among patients with advanced NSCLC who had progressed after one or two lines of therapy (11). The LEAP-006 phase 3 trial (NCT03829319) evaluates chemotherapy plus pembrolizumab with and without lenvatinib as first-line therapy in patients with non-squamous NSCLC. The LEAP-007 phase 3 trial (NCT03829332) compares pembrolizumab plus lenvatinib to pembrolizumab plus placebo in treatment-naïve patients with advanced PD-L1-positive NSCLC. In summary, anlotinib as single agent is a treatment option for pretreated patients with advanced NSCLC. Monotherapy with other VEGFR TKIs is not recommended. 1. Villaruz LC, Socinski MA. The role of anti-angiogenesis in non-small-cell lung cancer: an update. Curr Oncol Rep. 2015;17:26. 2. Liu L, Zhang Y, Wie J, et al. VEGFR-TKIs combined with chemotherapy for advanced non-small cell lung cancer: A systematic review. Journal of Cancer. 2019;10:799-809. 3. Lv WW, Zhang JJ, Zhou XL, et al. Safety of combining vascular endothelial growth factor receptor tyrosine-kinase inhibitors with chemotherapy in patients with advanced non-small-cell lung cancer. A PRISMA-compliant meta-analysis. Medicine. 2019; 98:23(e15806). 4. Lee JS, Hirsh V, Park K, et al. Vandetanib versus placebo in patients with advanced non-small-cell lung cancer after prior therapy with an epidermal growth factor receptor tyrosine kinase inhibitor: a randomized, double-blind phase III trial (ZEPHYR). J Clin Oncol. 2012;30:1114-1121. 5. Paz-Ares L, Hirsh V, Zhang L, et al. Monotherapy administration of sorafenib in patients with non-small cell lung cancer (MISSION) trial: a phase III, multicenter, placebo-controlled trial of sorafenib in patients with relapsed or refractory predominantly nonsquamous non-small-cell lung cancer after 2 or 3 previous treatment regimens. J Thorac Oncol. 2015;10:1745-1753. 6. Baggstrom MQ, Socinski MA, Wang XF, et al. Maintenance sunitinib following initial platinum-based combination chemotherapy in advanced-stage IIIB/IV non-small cell lung cancer: a randomized, double-blind, placebo-controlled phase III study - CALGB 30607 (Alliance). J Thorac Oncol. 2017;12:843-849. 7. Han B, Li K, Wang Q , et al. Effect of anlotinib as a third-line or further treatment on overall survival of patients with advanced non-small cell lung cancer: The ALTER 0303 phase 3 randomized clinical trial. JAMA Oncol. 2018;4:1569-1575. 8. Ma JT, Sun J, Sun L, et al. Efficacy and safety of apatinib in patients with advanced nonsmall cell lung cancer that failed prior chemotherapy or EGFR-TKIs. A pooled analysis. Medicine. 2018; 97:e12083. 9. Hao Z, Wang P. Lenvatinib in management of solid tumors. Oncologist. 2020;25:e302-e310. 10. Hida T, Velcheti V, Reckamp KL, et al. A phase 2 study of lenvatinib in patients with RET fusion-positive lung adenocarcinoma. Lung Cancer. 2019;138:124-130. 11. Brose MS, Vogelzang NJ, DiSimone C, et al. A phase Ib/II trial of lenvatinib plus pembrolizumab in non-small cell lung cancer. Journal of Clinical Oncology. 2019;37:8 (suppl, 16-16).

PURPOSE OF REVIEW The objective of this review is to discuss the strength and limitations of tissue and liquid biopsy and functional imaging to capture spatial and temporal tumor heterogeneity either alone or as part of a diagnostic framework in non-small cell lung cancer (NSCLC). RECENT FINDINGS NSCLC displays genetic and phenotypic heterogeneity - a detailed knowledge of which is crucial to personalize treatment. Tissue biopsy often lacks spatial and temporal resolution. Thus, NSCLC needs to be characterized by complementary diagnostic methods to resolve heterogeneity. Liquid biopsy offers detection of tumor biomarkers and for example, the classification and monitoring of EGFR mutations in NSCLC. It allows repeated sampling, and therefore, appears promising to address temporal aspects of tumor heterogeneity. Functional imaging methods and emerging image analytic tools, such as radiomics capture temporal and spatial heterogeneity. Further standardization of radiomics is required to allow introduction into clinical routine. SUMMARY To augment the potential of precision therapy, improved diagnostic characterization of tumors is pivotal. We suggest a comprehensive diagnostic framework combining tissue and liquid biopsy and functional imaging to address the known aspects of spatial and temporal tumor heterogeneity on the example of NSCLC. We envision how this framework might be implemented in clinical practice.

BACKGROUND:Osimertinib has become standard therapy of advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) patients and T790M-mediated resistance. We investigated the clinical utility of EGFR mutation tracking in plasma-based circulating tumor DNA (ctDNA) after start of osimertinib therapy in metastatic, EGFR-mutant NSCLC patients who had progressed on prior therapy with EGFR tyrosine kinase inhibitors (TKIs).METHODS:We enrolled 141 patients with advanced EGFR-mutated NSCLC who underwent second-line osimertinib treatment for T790M-positive disease. After initiation of osimertinib, we obtained plasma samples from 108 patients. Plasma ctDNA was tested for EGFR mutations by means of droplet digital PCR and was termed positive if any EGFR mutation was detected.RESULTS:Plasma ctDNA was detected in 58 of 108 (54%) patients after osimertinib initiation and was associated with poor progression-free survival (PFS) [hazard ratio (HR) 4.26, 95% confidence interval (CI): 2.55-7.10, P<0.0001] and overall survival (OS) (HR 3.23, 95% CI: 1.80-5.78, P<0.0001). In multivariable analysis, ctDNA status remained significantly associated with PFS and OS (HR 4.87, 95% CI: 2.81-8.44, P<0.0001; HR 3.49, 95% CI: 1.88-6.50, P<0.0001). Patients with persistence of activating EGFR mutations within eight weeks had shorter durations of PFS (HR 6.17, 95% CI: 3.03-12.56, P<0.0001) and OS (HR 4.83, 95% CI: 2.25-10.36, P<0.0001) than patients with total clearance of the activating EGFR mutation. Persistence of activating EGFR mutations in plasma ctDNA remained an independent predictor of poor PFS and OS in multivariable analyses.CONCLUSIONS:Patients with persistence of activating EGFR mutations in plasma ctDNA within eight weeks after osimertinib initiation have worse prognosis and may require the addition of chemotherapy or other treatments in order to achieve better outcome.

The knowledge on molecular alterations in lung cancer have increased during the last decade considerably. Almost every year new genes were detected being targetable, and drugs have been developed and provided for those patients being diagnosed with such a lung cancer. Therefore, it was necessary to update previous recommendations to facilitate a uniform handling for the diagnosis and molecular tests of lung cancer specimen all over Austria. Originally mutation of the epidermal growth factor receptor (EGFR) was the only actionable molecular alteration, now there are more than 10 driver mutations known, and more are detected, and clinical studies are performed. In addition, the technique to test for these mutations have improved, next generation sequencing has opened the option to test several genes in one test. Immuno-oncology has entered the field, and besides the checkpoint death receptor and ligand molecules PD-1/PD-L1 more molecules have been detected and are also tested in clinical studies. To provide equal opportunities to our patients the tests have to be implemented in all pathological institutes involved in lung cancer management. Because pathologists as part of the tumor board have to explain the diagnosis and the molecular alterations and suggest possible treatment options, the tests should be performed in-house, which will provide the optimal quality control.

S68 NSCLC with MET alterations: molecular insights and innovative treatments S72 Immune checkpoint inhibition: comprehensive benefits, but not devoid of risks S75 EGFR-mutated disease: early combinations and new approaches in exon 20 insertion-positive lung cancer S78 Improving outcomes in the early-stage setting with (neo)adjuvant strategies S81 Present and future perspectives of anti-angiogenic therapy S84 COVID-19 in patients with thoracic cancers: TERAVOLT S84 Rare mutations: HER2, RET, ALK, BRAF S87 Small-cell lung cancer: moving the limits further

Purpose of review The purpose of the review is to summarize the current and future role of chemotherapy in the treatment of patients with nonsmall cell lung cancer (NSCLC). Recent findings Chemotherapy has been established in early-stage, locally advanced and metastatic NSCLC. Patients with driver mutation-positive NSCLC receive tyrosine kinase inhibitors as first-line therapy and chemotherapy later during the course of their disease. Immune checkpoint inhibitors have entered clinical practice as single agents or in combination with chemotherapy. These novel treatments will supplement chemotherapy in all tumor stages of NSCLC. Targeted drugs and immune checkpoint inhibitors are gaining increasing importance in the treatment of NSCLC. They will supplement but not replace chemotherapy in the future.

Background. Management of non-small-cell lung cancer (NSCLC) is affected by regional specificities. The present study aimed at determining diagnostic and therapeutic procedures including outcome of patients with NSCLC stage III in the realworld setting in Central European countries to define areas for improvements. Patients and methods. This multicentre, prospective and non-interventional study collected data of patients with NSCLC stage III in a web-based registry and analysed them centrally. Results. Between March 2014 and March 2017, patients (n=583) with the following characteristics were entered: 32% females, 7% never-smokers; ECOG performance status (PS) 0, 1, 2 and 3 in 25%, 58%, 12% and 5%, respectively; 21% prior weight loss; 53% squamous carcinoma, 38% adenocarcinoma; 10% EGFR mutations. Staging procedures included chest X-ray (97% of patients), chest CT (96%), PET-CT (27%), brain imaging (20%), bronchoscopy (89%), endobronchial ultrasound (EBUS) (13%) and CT-guided biopsy (9%). Stages IIIA/IIIB were diagnosed in 55%/45% of patients, respectively. N2/N3 nodes were diagnosed in 60%/23% and pathologically confirmed in 29% of patients. Most patients (56%) were treated by combined modalities. Surgery plus chemotherapy was administered to 20%, definitive chemoradiotherapy to 34%, chemotherapy only to 26%, radiotherapy only to 12% and best supportive care (BSC) to 5% of patients. Median survival and progression-free survival times were 16.8 (15.3;18.5) and 11.2 (10.2;12.2) months, respectively. Stage IIIA, female gender, no weight loss, pathological mediastinal lymph node verification, surgery and combined modality therapy were associated with longer survival. Conclusions. The real-world study demonstrated a broad heterogeneity in the management of stage III NSCLC in Central European countries and suggested to increase the rates of PET-CT imaging, brain imaging and invasive mediastinal staging.

Detailed information regarding follow-up of ocular adnexal lymphoma and of the frequency of large cell transformation of low-grade ocular adnexal lymphoma is limited. We studied 174 patients with ocular adnexal lymphoma (OAL) to evaluate long-term clinical outcome and patterns of failure. All lymphomas presenting with involvement of the ocular adnexa diagnosed at the Massachusetts General Hospital (MGH) between 1974 and 2007, in which at least 6 months of follow-up was available, were included in this study. There were 106 extranodal marginal zone lymphomas (MALT lymphomas, MZL), 40 follicular lymphomas (FL), 16 diffuse large B cell lymphomas (DLBCL), 5 mantle cell lymphomas (MCL), 3 small lymphocytic lymphomas/chronic lymphocytic leukemias, 1 lymphoplasmacytic lymphoma, 2 B lymphoblastic lymphomas, and 1 extranodal NK/T cell lymphoma. Relapses occurred in 42 of 106 MZL patients (40%) and in 14 of 40 FL patients (35%). Two MZL and one FL progressed to DLBCL. Five and 10-year relapse-free survival (RFS) and five and 10-year overall survival (OS) respectively were: MZL 67%, 36%, 93%, 88%; FL: 54%, 32%, 90%, 82%; DLBCL: 79%, 79% 88%, 88% MCL: 20%, 0%, 100%, 25%. MZL and FL patients often developed relapses but had long survival; progression to DLBCL was uncommon. DLBCL had a favorable prognosis. MCL had a poor prognosis.