[Palliative aspects in pulmonary oncology]. / Palliativmedizinische Aspekte der Pneumo-Onkologie.

Palliative medicine is an essential part in the treatment of patients with advanced or metastatic NSCLC. A structured palliative approach beginning from diagnoses improves quality of life and maybe even prolong survival. Besides symptom control, the disease trajectory and prognosis should regularly be re-evaluated and discussed with the patient and his loved ones.

Comparative evaluation of PD-L1 expression in cytology imprints, circulating tumour cells and tumour tissue in non-small cell lung cancer patients.

Alternative sources of tumour information need to be explored in patients with non-small cell lung cancer (NSCLC). Here, we compared programmed cell death ligand 1 (PD-L1) expression on cytology imprints and circulating tumour cells (CTCs) with PD-L1 tumour proportion score (TPS) from immunohistochemistry staining of tumour tissue from patients with NSCLC. We evaluated PD-L1 expression using a PD-L1 antibody (28-8) in representative cytology imprints, and tissue samples from the same tumour. We report good agreement rates on PD-L1 positivity (TPS ≥ 1%) and high PD-L1 expression (TPS ≥ 50%). Considering high PD-L1 expression, cytology imprints showed a PPV of 64% and a NPV of 85%. CTCs were detected in 40% of the patients and 80% of them were PD-L1+ . Seven patients with PD-L1 expression of < 1% in tissue samples or cytology imprints had PD-L1+ CTCs. The addition of PD-L1 expression in CTCs to cytology imprints markedly improved the prediction capacity for PD-L1 positivity. A combined analysis of cytological imprints and CTCs provides information on the tumoural PD-L1 status in NSCLC patients, which might be used when no tumor tissue is available.

Immune Checkpoint Inhibition in Non-metastatic Non-small Cell Lung Cancer: Chance for Cure?

Immune checkpoint inhibition of programmed-death receptor 1 (PD-1) or its ligand (PD-L1) has become a standard in the treatment of metastatic non-small cell lung cancer, either as monotherapy or in combination. Recently, it could be shown that immunotherapy works as consolidation after chemoradiotherapy in locally advanced disease if the tumours express PD-L1. A significant and meaningful survival benefit for consolidation with durvalumab after chemoradiotherapy compared to chemoradiotherapy alone was observed in the PACIFIC trial. In addition, there is a growing body of evidence that this treatment modality is also effective in a neoadjuvant setting in early stages, whereas the role as adjuvant treatment after surgery needs to be determined. The impact of combination therapies in non-metastatic stages-either neoadjuvant or adjuvant-needs to be evaluated in future trials. It is yet unclear whether PD-L1 and tumour mutational burden are predictive biomarkers as randomised trials are missing.

Immune checkpoint blockade in small cell lung cancer.

Despite the highly immunogenic potential of small cell lung cancer (SCLC), progress in evaluating the therapeutic value of immune checkpoint agents has lagged behind that of non-small cell lung cancer. Results from a number of phase I-III clinical trials that specifically address the use of anti-PD-1, anti-PD-L1 and anti-CTLA-4 agents in SCLC have now been reported. This review will focus on the available evidence for immune checkpoint blockade in SCLC and review current biomarker strategies with the aim of providing perspective and interpretation of this data for clinical practice.

Redefining Treatment Paradigms in First-line Advanced Non-Small-Cell Lung Cancer.

Metastatic non-small-cell lung cancer is still a devastating disease; however, treatment options have diversified dramatically in the past two decades. From unselected platinum-based chemotherapy for all patients, several different treatment groups have evolved, that is, those with "druggable" targets, those with a promising immune signature, and those without any predicting factors outlined in this article. Challenge includes the intersections between these groups and the optimal treatment path. These issues will be addressed in this review.

Crizotinib.

Crizotinib is an ATP-competitive small-molecule inhibitor of the receptor tyrosine kinases (RTK) C-Met, ALK and ROS1. There is a robust effectiveness in non-small-cell lung cancer (NSCLC) harbouring EML4-ALK-rearrangements resulting in constitutional activation of the ALK-RTK. The drug is approved for this entity, which represents no more than 3-5% of all NSCLC. However, in this population, impressive response rates are generated. The same is true for ROS-1 rearrangements; however, these only occur in approximately 1% of all NSCLC. In small series, efficacy is also reported in patients, whose tumours harbour a MET Exon 4 skipping mutation (approx. 3% of all NSCLC). Toxicities include visual impairment, nausea, peripheral edema, QT-prolongation and liver-enzyme elevation. Also, the occurrence of renal cysts is reported. The detection of ALK-protein by immunohistochemistry is a predictor of efficacy for crizotinib. In cases of doubt, fluorescence in situ hybridisation (FISH) detecting the ALK-rearrangement has to be performed on tumour tissue. FISH is also the method of choice to detect ROS1-rearrangement, whereas MET-mutations are detected by sequencing methods. The high efficacy of crizotinib in ALK- and ROS-rearranged as well as MET mutated lung cancer as new molecular targets beside the epidermal growth factor receptor (EGFR) underscores the importance of molecular typing in NSCLC.

Advanced non-small cell lung cancer: the role of PD-L1 inhibitors.

PD-L1 and PD-1 inhibitors were both developed to combat a huge array of cancers. Both classes of agents block the PD-1/PD-L1 pathway. Unlike PD-1 inhibitors, PD-L1 inhibitors do also block the B-7.1-receptor and leave the PD-L2/PD-1 axis unaffected. Whether these differences enhance efficacy and tolerability is not clear yet. There are three PD-L1 inhibitors approved or in late clinical development: Atezolizumab, approved in 2nd-line treatment of non-small cell lung cancer, durvalumab, showing promising results as a consolidation therapy in stage III disease and avelumab, the only drug exploiting antigen-dependent cytotoxicity. Future directions are the combination of these compounds with chemotherapy or other immuno-oncologic drugs.

Efficacy and Safety of Nintedanib Plus Docetaxel in Patients with Advanced Lung Adenocarcinoma: Complementary and Exploratory Analyses of the Phase III LUME-Lung 1 Study.

BACKGROUND: Nintedanib is a triple angiokinase inhibitor approved with docetaxel for adenocarcinoma non-small cell lung cancer after first-line chemotherapy (FLT). In the phase III LUME-Lung 1 study, overall survival (OS) was significantly longer with nintedanib/docetaxel than with placebo/docetaxel in all adenocarcinoma patients and those with time from start of FLT (TSFLT) <9 months. OBJECTIVE: This study sought to extend analyses from the LUME-Lung 1 study, specifically for adenocarcinoma patients, to explore the impact of clinically relevant characteristics on outcomes such as time to progression after FLT. PATIENTS AND METHODS: Exploratory analyses were conducted of the overall and European LUME-Lung 1 adenocarcinoma population according to age, prior therapy, and tumor dynamics. Analyses also used TSFLT and time from end of FLT (TEFLT). RESULTS: Treatment with nintedanib/docetaxel significantly improved OS in European patients independently of age or prior therapy. Analyses of several patient subgroups showed improvements in median OS: TSFLT <6 months, 9.5 versus 7.5 months (hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.55-0.98); chemorefractory to FLT, 9.1 versus 6.9 months (HR 0.72, 95% CI 0.52-0.99); progressive disease (PD) as best response to FLT, 9.8 versus 6.3 months (HR 0.62, 95% CI 0.41-0.94); TEFLT ≤6 months, 11.3 versus 8.2 months (HR 0.75, 95% CI 0.61-0.92); and TEFLT <3 months, 11.0 versus 8.0 months (HR 0.74, 95% CI 0.58-0.94). CONCLUSIONS: Nintedanib/docetaxel demonstrated significant OS benefits in adenocarcinoma patients, which were more pronounced in patients with shorter TSFLT or TEFLT, or with PD as best response to FLT. This study was registered at ClinicalTrials.gov: NCT00805194.

[Chemotherapy in the Elderly with Non-Small Cell Lung Cancer: A Non-Interventional, Prospective, Multicentric Observational Study]. / Chemotherapie beim älteren Patienten mit nicht kleinzelligem Lungenkarzinom: Eine nicht-interventionelle, prospektive, multizentrische Beobachtungsstudie.

Background Elderly patients (70 years or older) with non-small cell lung cancer (NSCLC) do benefit from systemic chemotherapy as shown in many studies. We prospectively collected multicentric data on therapeutic decisions from patients 70 years or older to reflect the reality in the German health care system. Material and Methods Patients 70 years or older with NSCLC Stage IIIB or IV were eligible. No more than 20 consecutive patients from each center were included. Comorbidities, weighted by the Charlson-comorbidity-index, and survival data were collected. Results 253 patients were documented. Median age was 75.5 years (range 70 to 92) and 75 % were male. 2 % had no comorbidities, 5 % one, 15 % two, 24 % three and 55 % more than three. 237 patients (94 %) received systemic chemotherapy: 172 (73 %) as a combination and 58 (24 %) as monotherapy. Data from seven patients regarding therapy are missing. Combination regimens were in 66 % carboplatin- and in 30 % cisplatin-based. The most frequently given monotherapy was vinorelbin in 50 % of cases. In the group of the patients older than 80 years (n = 38), 53 % received mono therapy, 29 % a carboplatin-based regimen and 16 % no chemotherapy. Cisplatin was not administered in this age group. Median overall survival (OS) was 16.9 months. Patients with a Charlson-score ≤ 6 had 17.9 months, those > 6 12.0 months. With combination chemotherapy median OS was 23.5 months. Patients > 80 years had a median OS of 5.7 months. Conclusion A high percentage of patients older than 70 years received systemic therapy. Survival depended more on comorbidities than on age.

Second-Line Treatment Selection in Patients With Non-Small-Cell Lung Cancer of Adenocarcinoma Histology: Findings From a European Survey of Treating Physicians.

BACKGROUND: Guidelines provide treatment recommendations for advanced non-small-cell lung cancer (NSCLC), but physicians must also consider other factors. We surveyed physicians treating NSCLC to determine their therapy goals, drivers of treatment choice, current prescribing behavior, and therapy expectations. MATERIALS AND METHODS: In 2015, an online survey was conducted of 500 pulmonologists/oncologists treating lung adenocarcinoma in Germany, France, Italy, Spain, and the United Kingdom, comprising screening and therapy decision questions. RESULTS: On average, physicians had 14.7 years of experience and treated 79 patients/3 months with stage IIIb/IV NSCLC. In patients with Eastern Cooperative Oncology Group (ECOG) 0-1, "prolonged survival/extending life" was the main therapy goal of physicians for first- (63%) and second-line (40%) patients; improvement in quality of life (QoL) was the main goal of 14% of physicians for second-line patients. For patients with ECOG ≥2, the main goal of second-line therapy was improvement in QoL (26%) or tumor-related symptoms (23%). Most (57%) physicians strongly agreed that they preferred a second-line treatment that extends overall survival (OS) while maintaining QoL; their greatest dissatisfaction with available second-line treatment options was the inability to "stop tumor progression over the long term" (66%). Physicians expected new therapies to become available within 12 months that would provide improvements in progression-free survival (83%) or OS (69%). CONCLUSION: OS is important for second-line treatments in patients with stage IIIb/IV NSCLC, although QoL improvements should not be underestimated. This survey highlights the wait faced by patients and physicians as treatments transition from clinical trials to clinical practice.

Immunotherapy for small-cell lung cancer: emerging evidence.

Treatment for small-cell lung cancer (SCLC) has changed little over the past few decades; available therapies have failed to extend survival in advanced disease. In recent years, immunotherapy with treatments such as interferons, TNFs, vaccines and immune checkpoint inhibitors has advanced and shown promise in the treatment of several tumor types. Immune checkpoint inhibitors such as ipilimumab, nivolumab, pembrolizumab, durvalumab, tremelimumab and ulocuplumab are at the forefront of immunotherapy and have achieved approvals for certain cancer types, including melanoma (ipilimumab, nivolumab and pembrolizumab), non-SCLC (nivolumab and pembrolizumab) and renal cell carcinoma (nivolumab). Clinical trials are investigating different immunotherapies in patients with other solid and hematologic malignancies, including SCLC. We review emerging evidence supporting the use of immunotherapy in SCLC patients.

Measurement of quality of life in second-line patients with advanced NSCLC without targetable mutations: a review.

Quality of life (QoL) is important to cancer patients and is increasingly included as a trial end point. The methodologies/findings of randomized controlled trials evaluating the efficacy and safety of second-line treatments approved for use in the EU in patients with advanced/metastatic NSCLC, without known targetable mutations, were evaluated. Seven trials were identified; five compared active treatments and two compared active treatment to placebo. Methodologies used and reporting varied. The European Organization for Research and Treatment of Cancer lung cancer questionnaire was the most commonly used assessment method (n = 4). There was no evidence to suggest differences in QoL between active treatments. Consistent and appropriate use of standard QoL instruments in future would increase the reliability of results and their applicability to clinical decision-making.

Afatinib in Non-Small Cell Lung Cancer Harboring Uncommon EGFR Mutations Pretreated With Reversible EGFR Inhibitors.

BACKGROUND: Afatinib, an irreversible ErbB family blocker, is approved for treatment of patients with previously untreated non-small cell lung cancer (NSCLC) harboring activating epidermal growth factor receptor (EGFR) mutations. Efficacy of afatinib in EGFR tyrosine kinase inhibitor-naïve (TKI-naïve) patients with uncommon EGFR mutations (other than exon 19 deletions or exon 21 point mutations) has been reported; however, efficacy in TKI-pretreated patients with uncommon EGFR mutations is unknown. MATERIALS AND METHODS: In the afatinib compassionate use program (CUP), patients with advanced or metastatic, histologically confirmed NSCLC progressing after at least one line of chemotherapy and one line of EGFR-TKI treatment were enrolled. Demographic data, mutation type, response rates, time to treatment failure (TTF), and safety in patients harboring uncommon EGFR mutations were reported. RESULTS: In 60 patients (63% female, median age 63 years [range: 30-84 years]), a total of 66 uncommon EGFR mutations including 30 T790M mutations were reported (18.4% and 11%, respectively, of known EGFR mutations within the CUP). Most patients (67%) received afatinib as third- or fourth-line treatment. Median TTF was 3.8 months (range: 0.2 to >24.6 months; p = .244) in patients with uncommon mutations compared with 5.1 months (range: 0.1 to >21.1 months) in patients with common mutations (n = 165). Pronounced activity was observed with E709X mutations (TTF >12 months). No new safety signals were detected. CONCLUSION: Afatinib is clinically active and well tolerated in many TKI-pretreated NSCLC patients harboring uncommon EGFR mutations. Compared with results reported in TKI-naïve patients, activity was also indicated in patients with T790M and exon 20 insertion mutations.

Targeting of MEK in lung cancer therapeutics.

The MAP-kinase pathway, consisting of the kinases RAS, RAF, MEK, and ERK, is crucial for cell proliferation, inhibition of apoptosis, and migration of cells. Direct inhibition of RAS is not yet possible, whereas inhibition of RAF is already established in malignant melanoma and under investigation in non-small-cell lung cancer (NSCLC). Due to their structure and function, the MEK proteins are attractive targets for cancer therapy and are also under investigation in NSCLC. We discuss strategies of targeting the RAS-RAF-MEK-ERK pathway with emphasis on MEK inhibition, either alone or in combination with other targets or conventional chemotherapy.

[Non-small cell lung cancer: news from immunotherapy]. / Nicht-kleinzelliges Lungenkarzinom: Neues aus der Immuntherapie.

Immune evasion is recognized as a key strategy for survival and progression of several cancer entities including non-small cell lung cancer. Hence, various approaches to restore anti-tumor immune responses are currently investigated. In particular, agents targeting immune checkpoint receptors, such as the cytotoxic T-lymphocyte antigen-4 receptor and programmed death-1 receptor have shown promise in early clinical trials. With multiple studies under way, there are high expectations that treatment outcomes in patients with lung cancer who are ineligible for complete surgical resection may be improved with the incorporation of immunotherapies in the various treatment cascades.

Novel angiogenesis inhibitors in nonsmall cell lung cancer.

PURPOSE OF REVIEW: The fact that growth and spread of tumours are dependent on angiogenesis has led to the investigation of the role of antiangiogenic agents in the therapeutic strategies for thoracic tumours such as nonsmall cell lung cancer (NSCLC). This review summarizes and evaluates the recent developments in this field. RECENT FINDINGS: Bevacizumab, an antivascular endothelial growth factor antibody, has been approved for the treatment of patients with advanced NSCLC of nonsquamous histology in combination with a platinum-containing chemotherapy. Like in other cancer entities, the antiangiogenic concept in NSCLC comprises maintenance therapy with the antiangiogenic compound until disease progression. Moreover, over the last years, new antiangiogenic agents have been tested in clinical trials in NSCLC patients. Recent trials have demonstrated the efficacy of antiangiogenic agents in combination with docetaxel in the second-line setting. SUMMARY: These studies - together with experiences from other cancer entities - have revived the field of antiangiogenic treatment in lung cancer.