[Small Cell Lung Cancer]. / Kleinzelliges Lungenkarzinom.

Small cell lung cancer is an aggressive cancer entity and characterized by rapid progression, early distant metastasis and poor prognosis. Only the minority of patients presents with a non-metastatic stage disease where chemo-radiotherapy or - in very selected cases - even surgical resection may be discussed. For most patients, the efficacy of systemic therapy is crucial. However, although most patients respond to platinum doublet chemotherapy, virtually all patients with metastatic disease eventually develop tumor progression for which there are limited treatment options. Recently and for the first time since decades, the systemic approaches have been enriched by the implementation of immunotherapy. Moreover, novel therapeutic approaches such as new cytotoxic agents or further immune modulatory strategies are being tested in clinical studies that might broaden our treatment options in the future even further.

ARCTIC: durvalumab with or without tremelimumab as third-line or later treatment of metastatic non-small-cell lung cancer.

BACKGROUND: Many patients with metastatic non-small-cell lung cancer (mNSCLC) experience disease progression after first- and second-line treatment; more treatment options are required for these patients. ARCTIC, a phase III, randomized, open-label study, assessed durvalumab ± tremelimumab versus standard of care (SoC) as ≥ third-line treatment of mNSCLC. PATIENTS AND METHODS: ARCTIC comprised two independent sub-studies. Study A: 126 patients with ≥25% of tumor cells (TCs) expressing programmed cell death ligand-1 (PD-L1) were randomized (1 : 1) to durvalumab [up to 12 months 10 mg/kg every 2 weeks (q2w)] or SoC. Study B: 469 patients with PD-L1 TC <25% were randomized (3 : 2 : 2 : 1) to durvalumab + tremelimumab (12 weeks durvalumab 20 mg/kg + tremelimumab 1 mg/kg q4w then 34 weeks durvalumab 10 mg/kg q2w), SoC, durvalumab (up to 12 months 10 mg/kg q2w), or tremelimumab (24 weeks 10 mg/kg q4w then 24 weeks q12w). Primary end points: overall survival (OS) and progression-free survival (PFS) for durvalumab versus SoC (study A; descriptive only) and durvalumab + tremelimumab versus SoC (study B). RESULTS: Study A: median OS 11.7 (durvalumab) versus 6.8 (SoC) months {hazard ratio (HR) 0.63 [95% confidence interval (CI), 0.42-0.93]}; median PFS 3.8 (durvalumab) versus 2.2 (SoC) months [HR 0.71 (95% CI, 0.49-1.04)]. Study B: median OS 11.5 (durvalumab + tremelimumab) versus 8.7 (SoC) months [HR 0.80 (95% CI, 0.61-1.05); P = 0.109]. Median PFS of 3.5 months for both groups [HR 0.77 (95% CI, 0.59-1.01); P = 0.056]. Treatment-related grade 3/4 adverse events: 9.7% (durvalumab) and 44.4% (SoC; study A) and 22.0% (durvalumab + tremelimumab) and 36.4% (SoC; study B). CONCLUSIONS: In heavily pretreated patients with mNSCLC, durvalumab demonstrated clinically meaningful improvements in OS and PFS versus SoC (patients with PD-L1 TC ≥25%); numerical improvements in OS and PFS for durvalumab + tremelimumab versus SoC were observed (patients with PD-L1 TC <25%). Safety profiles were consistent with previous studies. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02352948.

[Joint Statement of the German Radiological Society and the German Respiratory Society on a Quality-Assured Early Detection Program for Lung Cancer with Low-dose CT]. / Positionspapier der Deutschen Röntgengesellschaft und der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin zu einem qualitätsgesicherten Früherkennungsprogramm des Lungenkarzinoms mittels Niedrigdosis-CT.

Substantial new data on early detection of lung cancer with low-dose CT has become available since the last joint statement of the German Roentgenological Society and the German Respiratory Society was published in 2011. The German S3 guideline on lung cancer was revised in 2018 and now contains a weak recommendation towards early detection of lung cancer with low-dose CT in a quality-assured early detection program. These new developments required a repositioning of the involved professional societies. This present joint statement describes main features of a quality-assured program for early detection of lung cancer with low-dose CT in Germany.

[Fundamental Changes in the Treatment of Lung Cancer]. / Klimawandel in der thorakalen Onkologie.

In recent years, the diagnosis and medical treatment of lung cancer patients has been changed profoundly. Still being a deadly disease for most patients, new developments in treatment approaches and therapy selection lead to significantly extended duration of disease control and overall survival. This development is evident not only in medical issues but also comprises various political and organisational aspects. These aspects will be briefly characterised and discussed in the following.

[Updated Recommendation for Treatment of Metastatic Non-Small Cell Lung Cancer]. / Aktualisierte Therapieempfehlung metastasiertes nicht kleinzelliges Lungenkarzinom.

Lung cancer accounts for the leading cause of cancer deaths in Germany and is characterized by early metastasis formation. The majority of patients with non-small cell lung cancer (NSCLC) will receive systemic therapy for treatment of their disease. Importantly together with the identification of targetable oncogenic alterations, systemic treatment of NSCLC has dramatically changed in recent years with the implementation of various new agents such as tyrosine kinase inhibitors and immune modulating drugs. However, these new therapeutic options also challenge the treating physician since molecular, histologic, and clinical factors need to be considered for the clinical decisionmaking. Moreover, supportive therapy including bronchoscopic therapy has evolved. The following therapy recommendations will summarize the up-to date treatment strategies for metastatic NSCLC.

[Rebiopsy for Patients with Lung Cancer - Joint Opinion from both the Endoscopic and Thoracic Oncology Sections of the German Society of Pneumology (DGP)]. / Empfehlung der Sektionen 2 und 11 der DGP zur Rebiopsie bei Lungenkarzinomen.

Performing rebiopsies for primary lung cancer and/or their metastases is becoming more and more prominent in daily practice, as the therapeutical spectrum increases and some newer strategies are dependent on immunohistochemical and/or molecular factors. In general, nearly all recurrent lesions or metastases can be reached. However, frequently invasive procedures are necessary with the need to carefully weigh risks and benefits of rebiopsies for the patient in each case. In this review indications for recurrent and progressive disease as well as risks are discussed and alternatives to rebiopsies are shown. This work is the joint opinion from both the endoscopic and thoracic oncology sections of the German Society of Pneumology (DGP).

Open-label, randomized study of individualized, pharmacokinetically (PK)-guided dosing of paclitaxel combined with carboplatin or cisplatin in patients with advanced non-small-cell lung cancer (NSCLC).

BACKGROUND: Variable chemotherapy exposure may cause toxicity or lack of efficacy. This study was initiated to validate pharmacokinetically (PK)-guided paclitaxel dosing in patients with advanced non-small-cell lung cancer (NSCLC) to avoid supra- or subtherapeutic exposure. PATIENTS AND METHODS: Patients with newly diagnosed, advanced NSCLC were randomly assigned to receive up to 6 cycles of 3-weekly carboplatin AUC 6 or cisplatin 80 mg/m(2) either with standard paclitaxel at 200 mg/m(2) (arm A) or PK-guided dosing of paclitaxel (arm B). In arm B, initial paclitaxel dose was adjusted to body surface area, age, sex, and subsequent doses were guided by neutropenia and previous-cycle paclitaxel exposure [time above a plasma concentration of 0.05 µM (Tc>0.05)] determined from a single blood sample on day 2. The primary end point was grade 4 neutropenia; secondary end points included neuropathy, radiological response, progression-free survival (PFS) and overall survival (OS). RESULTS: Among 365 patients randomly assigned, grade 4 neutropenia was similar in both arms (19% versus 16%; P = 0.10). Neuropathy grade ≥2 (38% versus 23%, P < 0.001) and grade ≥3 (9% versus 2%, P < 0.001) was significantly lower in arm B, independent of the platinum drug used. The median final paclitaxel dose was significantly lower in arm B (199 versus 150 mg/m(2), P < 0.001). Response rate was similar in arms A and B (31% versus 27%, P = 0.405), as was adjusted median PFS [5.5 versus 4.9 months, hazard ratio (HR) 1.16, 95% confidence interval (CI) 0.91-1.49, P = 0.228] and OS (10.1 versus 9.5 months, HR 1.05, 95% CI 0.81-1.37, P = 0.682). CONCLUSION: PK-guided dosing of paclitaxel does not improve severe neutropenia, but reduces paclitaxel-associated neuropathy and thereby improves the benefit-risk profile in patients with advanced NSCLC. CLINICAL TRIAL INFORMATION: NCT01326767 (https://clinicaltrials.gov/ct2/show/NCT01326767).

[Therapy of Metastatic Non-small Cell Lung Cancer]. / Therapieempfehlung für das metastasierte nicht-kleinzellige Lungenkarzinom.

Lung cancer accounts for the leading cause of cancer deaths in Germany and is characterized by early metastasis formation. The majority of patients with non-small cell lung cancer (NSCLC) will receive systemic therapy for treatment of their disease. Importantly together with the identification of targetable oncogenic alterations, systemic treatment of NSCLC has dramatically changed in recent years with the implementation of various new agents such as tyrosine kinase inhibitors, anti angiogenic agents, and immune modulating drugs. However, these new therapeutic options also challenge the treating physician since molecular, histologic, and clinical factors need to be considered for the clinical decision-making. Moreover, supportive therapy including bronchoscopic therapy has evolved. The following therapy recommendations will summarize the up-to date treatment strategies for metastatic NSCLC.

[ROS1-Translocations in Non-Small Cell Lung Cancer]. / ROS1-Translokationen im nicht-kleinzelligen Lungenkarzinom.

AIM: Summary of prevalence, testing and treatment approaches in patients with non-small cell lung cancer (NSCLC) and ROS1 activation. METHODS: Internet-based search for clinical and preclinical studies as well as search for ongoing studies in web-based databases. RESULTS: ROS1 translocations lead to tyrosine kinase activation and can be detected in 1 - 2% of all NSCLC and in 3 - 6% of pulmonary adenocarcinoma patients, respectively, using in situ hybridization techniques. RESULTS from phase I clinical studies using the ROS1 inhibitor crizotinib indicate response rates of 70 - 80% and a median progression-free survival of about 19 months. The therapy was generally well tolerated. CONCLUSIONS: NSCLC harbouring ROS1-translocations can be treated with targeted therapy leading to promising response and survival in patients. Hence, these alterations should be included into current molecular testing panels in stage IV pulmonary adenocarcinomas.

[Anti-angiogenic strategy: therapy optimization of non-squamous non-small cell lung carcinoma]. / Antiangiogenes Wirkprinzip--Konzepte der Therapieoptimierung des nicht-squamösen nicht-kleinzelligen Lungenkarzinoms.

Anti-angiogenic treatment with anti-VEGF compounds plays a central role in the therapy of non-squamous non-small cell lung cancer (NSCLC). However, biometric analysis of overall survival of the established treatment options reveals several limitations of efficacy in unselected patient cohorts. Furthermore, there are no established predictive biomarkers to help select patients who might benefit from this treatment option. This review focuses on underlying principles of action of tumor-related angiogenesis and presents new treatment options that may contribute to improved overall survival.

[A reduced TKI dosage is not associated with loss of activity in EGFR mutated NSCLC patients]. / Reduzierte Dosis von TKI führt nicht zu Wirkungsverlust bei Patienten mit aktivierender EGFR-Mutation.

BACKGROUND: Patients treated with anti-EGFR tyrosine kinase inhibitors (TKI) may receive dose reduction due to toxicity; however, the impact on treatment efficacy and patient outcome remains unknown. PATIENTS AND METHODS: Patients with stage IV NSCLC harbouring EGFR mutations and treated at our institution were retrospectively analyzed for treatment with TKI in 2012 or later. RESULTS: Thirty patients with EGFR mutated adenocarcinoma were identified meeting the inclusion criteria. Eleven patients received cytotoxic therapy as first line treatment yielding in a response rate of 36 %. All patients were treated with TKI as first or second-line therapy which resulted in disease stabilization (23 %) or response (77 %) in all patients. The median progression-free survival was 21.4 months with 21 patients still on treatment with TKI. For 7 patients, the dose of TKI treatment had to be reduced due to co-morbidities (n = 2) or skin toxicity (rash ≥ grade 3; n = 5). These patients demonstrated a similar response and outcome as compared to patients receiving full dose TKI treatment. CONCLUSION: Patients with EGFR mutated NSCLC and the need for TKI dose reduction seem to benefit in a similar manner from TKI therapy.

[Crizotinib - molecular therapy for lung cancer]. / Crizotinib - Molekulare Therapie des Lungenkarzinoms.

The anaplastic lymphoma kinase (ALK) can act as a key oncogenic driver after activation by means of processes such as gene rearrangement. In approximately 5 % of patients with advanced non-small cell lung cancer (NSCLC), an oncogenic fusion gene of echinoderm microtubule-associated protein-like 4 (EML4) and ALK has been detected using fluorescence in situ hybridisation (FISH). Moreover, various methods including immunohistochemistry and PCR-based assays can be used for analysing ALK expression. Clinical data have been generated for crizotinib, a small molecule inhibitor of the ALK receptor tyrosine kinase, demonstrating a substantial improvement of objective response rate and prolonged progression-free survival (PFS) compared to standard chemotherapy in pretreated NSCLC patients harbouring EML4-ALK fusion genes. In the current review, recent data on the detection and inhibition of ALK in advanced NSCLC are summarised.

[New developments in treatment of non-small cell lung cancer]. / Aktuelle Entwicklungen in der Therapie des nicht-kleinzelligen Lungenkarzinoms.

In early June the annual meeting of the American Society of Clinical Oncology (ASCO) took place. Several new hypotheses, therapy approaches and clinical studies were presented and intensively discussed. Some new developments in treatment of non-small cell lung cancer will be briefly discussed in this article.

Durvalumab, with or without tremelimumab, plus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer: 3-year overall survival update from CASPIAN.

BACKGROUND: In the phase III CASPIAN study, first-line durvalumab in combination with etoposide plus either cisplatin or carboplatin (EP) significantly improved overall survival (OS) versus EP alone in extensive-stage small-cell lung cancer (ES-SCLC). Durvalumab plus tremelimumab plus EP numerically improved OS versus EP, but did not reach statistical significance. Here we report updated OS in censored patients after median follow-up of >3 years. PATIENTS AND METHODS: 805 patients with treatment-naïve ES-SCLC were randomized 1 : 1 : 1 to durvalumab plus EP, durvalumab plus tremelimumab plus EP, or EP. The two primary endpoints were OS for durvalumab plus EP versus EP and for durvalumab plus tremelimumab plus EP versus EP. RESULTS: As of 22 March 2021 (median follow-up 39.4 months, 86% maturity), durvalumab plus EP continued to demonstrate improved OS versus EP: hazard ratio (HR) 0.71 [95% confidence interval (CI) 0.60-0.86; nominal P = 0.0003]; median OS was 12.9 versus 10.5 months, and 36-month OS rate was 17.6% versus 5.8%. Durvalumab plus tremelimumab plus EP continued to numerically improve OS versus EP: HR 0.81 (95% CI: 0.67-0.97; nominal P = 0.0200); median OS was 10.4 months, and 36-month OS rate was 15.3%. Twenty-seven and nineteen patients in the durvalumab plus EP and durvalumab plus tremelimumab plus EP arms, respectively, remained on durvalumab treatment at data cut-off. CONCLUSIONS: Three times more patients were estimated to be alive at 3 years when treated with durvalumab plus EP versus EP, with the majority still receiving durvalumab at data cut-off, further establishing durvalumab plus EP as first-line standard of care for ES-SCLC.

[Treatment of non-small cell lung cancer]. / Behandlung des nichtkleinzelligen Lungenkarzinoms.

Within recent years, the treatment of non-small cell lung cancer has become increasingly heterogeneous and complex. New cytotoxic agents and drugs against molecular targets have been developed. Moreover, new indications for therapy such as maintenance therapy have been explored. In addition, by assessing defined molecular markers, it is possible to identify patients who may likely respond to a given treatment. This approach will continue in the future; thus, it will be possible to characterize patient into subgroups based on molecular, histological, or clinical markers. This review will summarize the current state of the art in the treatment of non-small cell lung cancer.

Current data on predictive markers for anti-angiogenic therapy in thoracic tumours.

The fact that growth and spread of tumours are dependent on angiogenesis has led to the investigation of the role of anti-angiogenic agents in the therapeutic strategies for thoracic tumours such as nonsmall cell lung cancer or mesotheliomas. Since various angiogenic factors may contribute to the regulation of angiogenesis in the individual tumour, in the era of increasing amounts of clinically tested agents it is of utmost importance to properly select patients that may benefit from a specific therapy. Due to the complex nature of tumour angiogenesis, various biomarkers may be applicable. For example, the profile of activated angiogenic pathways in endothelial cells may be determined in order to make conclusions about the relevance of inhibiting a given pathway by a selected agent. Moreover, changes in protein expression in stromal and tumour cells, as well as structural alterations in the vasculature, may be used for predicting and monitoring the clinical effects of such a therapy. In this review, the current data from clinical studies evaluating predictive markers for anti-angiogenic agents in thoracic cancers are summarised. Besides giving clinical examples, the rationales for investigating various parameters based on pre-clinical studies are described.

[New strategies for NSCLC: is inhibition of tumour vasculature useful]. / Neue Strategien beim NSCLC: Was bringt die Hemmung der Tumorgefässe?

Lung cancer is the leading cause of cancer-related mortality in Germany. Improvements in our understanding of cancer biology have led to the development of novel agents that inhibit the tumour vasculature in order to induce subsequent tumour cell death. In this context, the inhibition of tumour-related angiogenesis - the growth of new vessels from pre-existing vessels - has become an attractive target for anticancer therapy. Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), has already been approved in combination with platinum-based chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) without predominant squamous cell histology. Moreover, small molecule inhibitors targeting multiple angiogenic receptors have also shown promise when combined with standard chemotherapy. As a different approach, vascular disrupting agents (VDAs) have been designed to particularly target preexisting blood vessels which may lead to a vascular shut-down. In the present review, both principles of action and current clinical data on anti-angiogenic agents and VDAs in the treatment of patients with NSCLC are reviewed.