Activity of afatinib in patients with NSCLC harboring novel uncommon EGFR mutations with or without co-mutations: a case report.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represent first-line standard of care in unresectable EGFR mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC). However, 10-20% of patients with EGFRm+ NSCLC have uncommon EGFR variants, defined as mutations other than L858R substitutions or exon 19 deletions. NSCLC harboring uncommon EGFR mutations may demonstrate lower sensitivity to targeted agents than NSCLC with L858R or exon 19 deletion mutations. Prospective clinical trial data in patients with NSCLC uncommon EGFR mutations are lacking. Afatinib is a second-generation TKI and the only Food and Drug Administration-approved drug for some of the more prevalent uncommon EGFR mutations. We present a series of seven case reports describing clinical outcomes in afatinib-treated patients with NSCLC harboring a diverse range of extremely rare mutations with or without co-mutations affecting other genes. EGFR alterations included compound mutations, P-loop αC-helix compressing mutations, and novel substitution mutations. We also present a case with NSCLC harboring a novel EGFR::CCDC6 gene fusion. Overall, the patients responded well to afatinib, including radiologic partial responses in six patients during treatment. Responses were durable for three patients. The cases presented are in line with a growing body of clinical and preclinical evidence that indicating that NSCLC with various uncommon EGFR mutations, with or without co-mutations, may be sensitive to afatinib.

Sotorasib in KRAS G12C-mutated non-small cell lung cancer: A multicenter real-world experience from the compassionate use program in Germany.

BACKGROUND: Sotorasib is a first-in-class KRAS p.G12C-inhibitor that has entered clinical trials in pretreated patients with non-small cell lung cancer (NSCLC) in 2018. First response rates were promising in the CodeBreaK trials. It remains unclear whether response to sotorasib and outcomes differ in a real-world setting when including patients underrepresented in clinical trials. METHODS: Patients with KRAS p.G12C-mutated advanced or metastatic NSCLC received sotorasib within the German multicenter sotorasib compassionate use program between 2020 to 2022. Data on efficacy, tolerability, and survival were analyzed in the full cohort and in subgroups of special interest such as co-occurring mutations and across PD-L1 expression levels. RESULTS: We analyzed 163 patients who received sotorasib after a median of two treatment lines (range, 0 to 7). Every fourth patient had a poor performance status and 38% had brain metastases (BM). The objective response rate was 38.7%. The median overall survival was 9.8 months (95% CI, 6.5 to not reached). Median real-world (rw) progression-free survival was 4.8 months (9% CI, 3.9 to 5.9). Dose reductions and permanent discontinuation were necessary in 35 (21.5%) and 7 (4.3%) patients, respectively. Efficacy seems to be influenced by PD-L1 expression and a co-occurring KEAP1 mutation. KEAP1 was associated with an inferior survival. Other factors such as BM, STK11, and TP53 mutations had no impact on response and survival. CONCLUSION: First results from a real-world population confirm promising efficacy of sotorasib for the treatment of advanced KRAS p.G12C-mutated NSCLC. Patients with co-occurring KEAP1 mutations seem to derive less benefit.

The Combined Therapy of Cabozantinib, Crizotinib, and Osimertinib in a Lung Cancer Patient with Acquired MET Amplification and Resistance Mutations.

EGFR-mutant lung cancers develop a wide range of potential resistance alterations under therapy with the third-generation EGFR tyrosine kinase inhibitor osimertinib. MET amplification ranks among the most common acquired resistance alterations and is currently being investigated as a therapeutic target in several studies. Nevertheless, targeted therapy of MET might similarly result in acquired resistance by point mutations in MET, which further expands therapeutic and diagnostic challenges. Here, we report a 50-year-old male patient with EGFR-mutant lung adenocarcinoma and stepwise acquired resistance by a focal amplification of MET followed by D1246N (D1228N), D1246H (D1228H), and L1213V (L1195V) point mutations in MET, all detected by NGS. The patient successfully responded to the combined and sequential treatment of osimertinib, osimertinib/crizotinib, and third-line osimertinib/cabozantinib. This case highlights the importance of well-designed, sequential molecular diagnostic analyses and the personalized treatment of patients with acquired resistance.

NSCLC with uncommon EGFR mutations treated with atezolizumab plus bevacizumab and chemotherapy.

OBJECTIVES: For refractory NSCLC patients with EGFR mutations, recent studies have demonstrated a favorable response to the combination of anti-angiogenic therapy and checkpoint inhibition but included only very few patients with uncommon EGFR mutations for which treatment options are still limited despite new targeted treatments. MATERIALS AND METHODS: Sixteen stage IV NSCLC patients with uncommon EGFR mutations from 9 different German centers were treated in first or further line with Atezolizumab, Bevacizumab, Carboplatin and (nab-)Paclitaxel (ABCP). PFS was evaluated from start of ABCP and OS from time of initial diagnosis of stage IV. RESULTS: Patients with either an Exon 20 insertion (n = 9) or other uncommon EGFR mutations (n = 7) received ABCP in first, second or further line. Nine patients had received a TKI therapy in first line with an ORR of 66.7 % and a median time-to-next-treatment of 6.7 months. After a median number of 4 ABCP cycles, 4 patients (25.0 %) required a dose reduction of chemotherapy and 5 patients (31.3 %) suffered from grade 3 or 4 toxicity. Overall response rate was 81.3 % and disease control rate 87.5 %. 14 patients (87.5 %) received a maintenance with AB and the median follow-up after initial diagnosis was 24.3 months. Median PFS was 13.6 months for both the entire cohort and for Exon 20 insertions. Corresponding median OS was either not reached or 30.7 months. Landmark analysis at 12 months gave a PFS of 42.8 % and an OS of 93.3 %. Four patients were rechallenged with ABCP while progressing under maintenance and responded again. In further line therapy, clinical benefit was achieved in all of 3 patients receiving Amivantamab, but in only one of four patients receiving mobocertinib. CONCLUSION: In this retrospective analysis, ABCP achieves an encouraging outcome for patients with uncommon EGFR mutations and is a valuable option in the early treatment course.

Clinical Post-SARS-CoV-2 Infection Scenarios in Vaccinated and Non-Vaccinated Cancer Patients in Three German Cancer Centers: A Retrospective Analysis.

COVID-19 vaccines have become an integral element in the protection of cancer patients against SARS-CoV-2. To date, there are no direct comparisons of the course of COVID-19 infection in cancer patients between the pre- and post-vaccine era. We analyzed SARS-CoV-2 infections and their impact on cancer in COVID-19 vaccinated and non-vaccinated patients from three German cancer centers. Overall, 133 patients with SARS-CoV-2 were enrolled in pre- and post-vaccine eras: 84 non-vaccinated and 49 vaccinated, respectively. A mild course of COVID-19 was documented more frequently in vaccinated patients (49% vs. 29%), while the frequency of severe and critical courses occurred in approximately one-half of the non-vaccinated patients (22% vs. 42%, p = 0.023). Particularly, patients with hematologic neoplasms benefited from vaccination in this context (p = 0.031). Admissions to intermediate- and intensive-care units and the necessity of non-invasive and invasive respiratory support were reduced by 71% and 50% among vaccinated patients, respectively. The median length of admission was 11 days for non-vaccinated and 5 days for vaccinated patients (p = 0.002). COVID-19 mortality was reduced by 83% in vaccinated patients (p = 0.046). Finally, the median time from SARS-CoV-2 infection to restarting cancer therapy was 12 and 26 days among vaccinated and non-vaccinated groups, respectively (p = 0.002). Although this study does not have enough power to perform multivariate analyses to account for confounders, it provides data on COVID-19 in non-vaccinated and vaccinated cancer patients and illustrates the potential benefits of COVID-19 vaccines for these patients.

Comparison of Resistance Spectra after First and Second Line Osimertinib Treatment Detected by Liquid Biopsy.

Since 2009, several first, second, and third generation EGFR tyrosine kinase inhibitors (TKI) have been approved for targeted treatment of EGFR mutated metastatic non-small lung cancer (NSCLC). A vast majority of patients is improving quickly on treatment; however, resistance is inevitable and typically occurs after one year for TKI of the first and second generation. Osimertinib, a third generation TKI, has recently been approved for first line treatment in the palliative setting and is expected to become approved for the adjuvant setting as well. Progression-free survival (PFS) under osimertinib is superior to its predecessors but its spectrum of resistance alterations appears significantly more diverse compared to first and second generation EGFR TKI. As resistance mechanisms to osimertinib are therapeutically targetable in some cases, it is important to comprehensively test for molecular alterations in the relapse scenario. Liquid biopsy may be advantageous over tissue analysis as it has the potential to represent tumor heterogeneity and clonal diversification. We have previously shown high concordance of hybrid capture (HC) based next generation sequencing (NGS) in liquid biopsy versus solid tumor biopsies. In this study, we now present real-word data from 56 patients with metastatic NSCLC that were tested by liquid biopsy at the time of disease progression on mostly second line treated osimertinib treatment. We present examples of single and multiple TKI resistance mechanisms, including mutations in multiple pathways, copy number changes and rare fusions of RET, ALK, FGFR3 and BRAF. In addition, we present the added value of HC based NGS to reveal polyclonal resistance development at the DNA level encoding multiple EGFR C797S and PIK3CA mutations.

Diagnostic, Clinical and Post-SARS-CoV-2 Scenarios in Cancer Patients with SARS-CoV-2: Retrospective Analysis in Three German Cancer Centers.

Oncologists face challenges in the management of SARS-CoV-2 infections and post-SARS-CoV-2 cancer treatment. We analyzed diagnostic, clinical and post-SARS-CoV-2 scenarios in patients from three German cancer centers with RT-PCR confirmed SARS-CoV-2 infection. Sixty-three patients with SARS-CoV-2 and hematologic or solid neoplasms were included. Thirty patients were initially asymptomatic, 10 of whom developed COVID-19 symptoms subsequently. Altogether 20 (32%) patients were asymptomatic, 18 (29%) had mild, 12 (19%) severe and 13 (20%) critical courses. Lymphocytopenia increased risk of severe/critical COVID-19 three-fold (p = 0.015). Asymptomatic course was not associated with age, remission status, therapies or co-morbidities. Secondary bacterial infection accompanied more than one third of critical COVID-19 cases. Treatment was delayed post-SARS-CoV-2 in 46 patients, 9 of whom developed progressive disease (PD). Cancer therapy was modified in 8 SARS-CoV-2 survivors because of deteriorating performance or PD. At the last follow-up, 17 patients had died from COVID-19 (n = 8) or PD (n = 9) giving an estimated 73% four-month overall survival rate. SARS-CoV-2 infection has a heterogenous course in cancer patients. Lymphocytopenia carries a significant risk of severe/critical COVID-19. SARS-CoV-2 disruption of therapy is as serious as SARS-CoV-2 infection itself. Careful surveillance will allow early restart of the anti-cancer treatment.

Efficacy of docetaxel plus ramucirumab as palliative second-line therapy following first-line chemotherapy plus immune-checkpoint-inhibitor combination treatment in patients with non-small cell lung cancer (NSCLC) UICC stage IV.

BACKGROUND: Chemotherapy plus immune-checkpoint inhibitor (CTx+ICI) therapy has become the preferred 1st line treatment in patients with metastatic NSCLC without oncogenic driven mutations. However, the optimal subsequent 2nd line treatment is not defined and several alternatives exist. The purpose of this analysis was to evaluate the efficacy of 2nd line docetaxel plus ramucirumab (D+R) initiated after failure of 1st line CTx+ICI. METHODS: Retrospective data were collected during routine care from German thoracic oncology centers. Only patients who had received at least one course of 2nd line D+R were included. ORR, PFS, OS and numbers of courses of D+R were investigated with PFS after initiation of D+R being the primary endpoint. RESULTS: Seventy-seven patients met the inclusion criteria. 2nd line treatment with D+R achieved an ORR and DCR of 32.5% and 62.4%, respectively. Median PFS for 2nd line therapy was 3.9 months with a DOR of 6.4 months. Median OS of 15.5 and 7.5 months were observed from the start of 1st line therapy and 2nd line treatment, respectively. No unexpected toxicities occurred. Presence of KRAS mutations was associated with significantly worse median PFS to D+R (2.8 vs. 4.5 months in wild-type cases; P=0.021) and was an independent predictor of inferior PFS in multivariate analysis. CONCLUSIONS: D+R is an effective and safe 2nd line treatment after failure of 1st line CTx+ICI irrespective of NSCLC histology. However, patients with a KRAS mutation did not benefit from D+R in terms of PFS and will require further investigations.

Durvalumab after definitive chemoradiotherapy in locally advanced NSCLC: Data of the German EAP.

Following the PACIFIC trial, durvalumab has been approved by the European Medicines Agency (EMA) for consolidation of locally advanced PD-L1-positive NSCLC after chemoradiotherapy (CRT). Patients were treated with durvalumab in the EAP from 22.11.2017 to 15.10.2018 allowing analysis of its efficacy and safety. 211 patients were registered by 90 German centres. Data were collected retrospectively by questionnaire and queries. 56 centres reported data on 126 patients who actually received at least one cycle of durvalumab. In contrast to the PACIFIC-trial population, some patients with oligometastatic disease and a history of autoimmune disease are included in the EAP population. Information on PD-L1 status was obtained for 111 patients. Baseline data include age, gender, ECOG, stage (IASLC 8th ed.), and smoking history. Treatment data include mode of chemoradiotherapy, used chemotherapy agent, and duration of durvalumab therapy. Adverse evants were documented according to CTAEC 5.0. Data were analysed for progression-free survival (PFS), overall survival (OS), and adverse events (AE). The results were published in Lung Cancer [1].

KRAS G12C-mutated advanced non-small cell lung cancer: A real-world cohort from the German prospective, observational, nation-wide CRISP Registry (AIO-TRK-0315).

OBJECTIVES: After decades of unsuccessful efforts in inhibiting KRAS, promising clinical data targeting the mutation subtype G12C emerge. Since little is known about outcome with standard treatment of patients with G12C mutated non-small cell lung cancer (NSCLC), we analyzed a large, representative, real-world cohort from Germany. PATIENTS AND METHODS: A total of 1039 patients with advanced KRAS-mutant or -wildtype NSCLC without druggable alterations have been recruited in the prospective, observational registry CRISP from 12/2015 to 06/2019 by 98 centers in Germany. Details on treatment, best response, and outcome were analyzed for patients with KRAS wildtype, G12C, and non-G12C mutations. RESULTS: Within the study population, 160 (15.4 %) patients presented with KRAS G12C, 251 (24.2 %) with non-G12C mutations, 628 (60.4 %) with KRAS wildtype. High PD-L1 expression (Tumor Proportion Score, TPS > 50 %) was documented for 28.0 %, 43.5 %, and 28.9 % (wildtype, G12C, non-G12C) of the tested patients; 68.8 %, 89.3 %, and 87.7 % of the patients received first-line treatment combined with an immune checkpoint-inhibitor in 2019. TPS > 50 % vs. TPS < 1 % was associated with a significantly decreased risk of mortality in a multivariate Cox model (HR 0.39, 95 % CI 0.26-0.60, p=<0.001). There were no differences in clinical outcome between KRAS wildtype, G12C or non-G12C mutations and KRAS mutational status was not prognostic in the model. CONCLUSION: Here we describe the so far largest prospectively recruited cohort of patients with advanced NSCLC and KRAS mutations, with special focus on the G12C mutation. These data constitute an extremely valuable historical control for upcoming clinical studies that employ KRAS inhibitors.

Durvalumab after definitive chemoradiotherapy in locally advanced unresectable non-small cell lung cancer (NSCLC): Real-world data on survival and safety from the German expanded-access program (EAP).

BACKGROUND: Following the PACIFIC trial, durvalumab has been approved by the European Medicines Agency (EMA) for consolidation of locally advanced PD-L1-positive NSCLC after chemoradiotherapy (CRT). Patients were treated with durvalumab in the EAP from 22.11.2017 to 15.10.2018 allowing analysis of its efficacy and safety. METHODS: Data from 56 centres were analysed for adverse events (AE), progression-free survival (PFS), overall survival (OS). RESULTS: 126 patients actually received at least 1 cycle durvalumab. Compared to the PACIFIC trial, the EAP population had more advanced stage and included "oligometastatic" stage IV patients and patients with autoimmune disease. PFS (20.1 months) and OS (not reached) were similar in the EAP and the PACIFIC trial. 42.9 % completed 12 months of durvalumab without deaths during FU. Stage IV patients (n = 7) had encouraging OS (not reached at 27 months). Autoimmune disease did not affect survival. PFS and OS were similar in PD-L1-negative patients (n = 32) and PD-L1-positive patients (n = 79). CONCLUSIONS: Survival in the EAP was comparable to the PACIFIC trial. Selected stage IV patients and patients with autoimmune disease may benefit from durvalumab consolidation and should be included in future immuno-oncological trials. PD-L1 did not predict survival challenging the exclusion of PD-L1-negative patients from durvalumab consolidation. In summary, durvalumab consolidation is safe and effective in a European real-world setting.

Efficacy of Docetaxel Plus Ramucirumab as Palliative Third-Line Therapy Following Second-Line Immune-Checkpoint-Inhibitor Treatment in Patients With Non-Small-Cell Lung Cancer Stage IV.

BACKGROUND: Antiangiogenic agents have been shown to stimulate the immune system and cause synergistic effects with chemotherapy. Effects might be even stronger after immune-checkpoint-inhibitor (ICI) therapy. The purpose of this analysis was to evaluate the efficacy of ramucirumab plus docetaxel (R + D) as third-line treatment after failure of a first-line platinum-based chemotherapy and a second-line ICI treatment in patients with non-small-cell lung cancer (NSCLC) stage IV. METHODS: Retrospective data were collected from 9 German thoracic oncology centers. Only patients who had received at least 1 cycle of third-line R + D were included. The numbers of cycles, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were investigated. RESULTS: Sixty-seven patients met the criteria for inclusion. Third-line treatment with R + D achieved an ORR of 36% and a disease control rate (DCR) of 69%. Median PFS for third-line therapy was 6.8 months with a duration of response (DOR) of 10.2 months. A median OS of 29 months was observed from the start of first-line therapy with a median OS of 11.0 months from the start of third-line treatment. No unexpected toxicities occurred. CONCLUSION: R + D is a highly effective and safe third-line treatment after failure of second-line programmed cell death protein 1/programmed cell death-ligand 1 (PD1/PD-L1)-derived ICI therapy irrespective of NSCLC histology. As there may be synergistic effects of second- and third-line treatments, this sequence is a very suitable option for patients not treated with first-line ICI. In addition, R + D should continue to be investigated as a second-line treatment option after failure of chemotherapy plus ICI in the palliative first-line treatment.

Integration of Tumor Mutation Burden and PD-L1 Testing in Routine Laboratory Diagnostics in Non-Small Cell Lung Cancer.

In recent years, Non-small cell lung cancer (NSCLC) has evolved into a prime example for precision oncology with multiple FDA-approved "precision" drugs. For the majority of NSCLC lacking targetable genetic alterations, immune checkpoint inhibition (ICI) has become standard of care in first-line treatment or beyond. PD-L1 tumor expression represents the only approved predictive biomarker for PD-L1/PD-1 checkpoint inhibition by therapeutic antibodies. Since PD-L1-negative or low-expressing tumors may also respond to ICI, additional factors are likely to contribute in addition to PD-L1 expression. Tumor mutation burden (TMB) has emerged as a potential candidate; however, it is the most complex biomarker so far and might represent a challenge for routine diagnostics. We therefore established a hybrid capture (HC) next-generation sequencing (NGS) assay that covers all oncogenic driver alterations as well as TMB and validated TMB values by correlation with the assay (F1CDx) used for the CheckMate 227 study. Results of the first consecutive 417 patients analyzed in a routine clinical setting are presented. Data show that fast reliable comprehensive diagnostics including TMB and targetable alterations are obtained with a short turn-around time. Thus, even complex biomarkers can easily be implemented in routine practice to optimize treatment decisions for advanced NSCLC.

Effect of preoperative chemoradiation in addition to preoperative chemotherapy: a randomised trial in stage III non-small-cell lung cancer.

BACKGROUND: Preoperative chemotherapy improves survival in patients with stage III non-small-cell lung cancer (NSCLC) amenable to resection. We aimed to assess the additional effect of preoperative chemoradiation on tumour resection, pathological response, and survival in these patients. METHODS: Between Oct 1, 1995, and July 1, 2003, patients with stage IIIA-IIIB NSCLC and invasive mediastinal assessment from 26 participating institutions of the German Lung Cancer Cooperative Group (GLCCG) were randomly assigned to one of two treatment groups. The intervention group were scheduled to receive three cycles of cisplatin and etoposide, followed by twice-daily radiation with concurrent carboplatin and vindesine, and then surgical resection (those with positive resection margins or unresectable disease were offered further twice-daily radiotherapy). The control group were scheduled to receive three cycles of cisplatin and etoposide, followed by surgery, and then further radiotherapy. The primary endpoint was median progression-free survival (PFS) in patients eligible for treatment after randomisation. Secondary endpoints in patients eligible for treatment after randomisation were overall survival (OS) and the proportion of patients undergoing surgery. Secondary endpoints in patients with tumour resection were the proportion with negative resection margins, the proportion with complete resection, the proportion with histopathological response, and the proportion with mediastinal downstaging. Additionally, exploratory (not prespecified) post-hoc analyses in terms of PFS and OS were done on patients not amenable to resection and on further subgroups of patients undergoing resection. Analyses were by intention to treat. This trial is registered on the ClinicalTrials.gov website, number NCT 00176137. FINDINGS: 558 patients were randomly assigned. 34 patients did not meet inclusion criteria and were excluded. Of 524 eligible patients, 142 of 264 (54%) in the interventional group and 154 of 260 (59%) in the control group underwent surgery; 98 of 264 (37%) and 84 of 260 (32%) underwent complete resection. In patients with complete resection, the proportion of those with mediastinal downstaging (45 of 98 [46%] and 24 of 84 [29%], p=0.02) and pathological response (59 of 98 [60%] and 17 of 84 [20%], p<0.0001) favoured the interventional group. However, there was no difference in PFS (primary endpoint) between treatment groups-either in eligible patients (median PFS 9.5 months, range 1.0-117.0 [95% CI 8.3-11.2] vs 10.0 months, range 1.0-111.0 [8.9-11.5], 5-year PFS 16% [11-21] vs 14% [10-19], hazard ratio (HR) 0.99 [0.81-1.19], p=0.87), in those undergoing tumour resection, or in patients with complete resection. In both groups, 35% of patients undergoing surgery received a pneumonectomy (50/142 vs 54/154). In patients receiving a pneumonectomy, treatment-related mortality increased in the interventional group compared with the control group (7/50 [14%] vs 3/54 [6%]). INTERPRETATION: In patients with stage III NSCLC amenable to surgery, preoperative chemoradiation in addition to chemotherapy increases pathological response and mediastinal downstaging, but does not improve survival. After induction with chemoradiation, pneumonectomy should be avoided. FUNDING: German Cancer Aid (Bonn, Germany).

First-line systemic treatment with gefitinib in stage IV non-small cell lung cancer.

Lung cancer has a high mortality rate and is often diagnosed in locally advanced or metastatic stages. A new therapeutic option for patients with non-small cell lung cancer (NSCLC) in these stages with progress or relapse after platinum-based chemotherapy exists in the inhibitors of the epidermal growth factor receptor (EGFR) tyrosine-kinase. EGFR tyrosine-kinase inhibitor treatment might also be an option for patients ineligible for surgery and conventional chemotherapy. We present a case of a 53-year-old woman who was diagnosed due to pain from multiple bone metastases of a lung adenocarcinoma. She refused cytotoxic chemotherapy, and we administered first-line systemic treatment with gefitinib subsequent to radiotherapy of metastatic bone disease. The patient responded well to gefitinib treatment and achieved a partial response after 3 weeks. No relevant side effects occurred, and the patient experienced an 8-month remission of disease. With a follow-up of 10 months, the patient is still alive. Retrospectively, we found a mutation of the EGF receptor in tumor cells of the patient, which is associated with sensitivity to gefitinib. EGFR tyrosine-kinase inhibitors (TKI) can be an alternative first-line systemic treatment option for selected patients with metastatic NSCLC.

Efficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-pretreated non-small-cell lung cancer patients with brain metastases or leptomeningeal disease.

INTRODUCTION: Afatinib is an effective first-line treatment in patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) and has shown activity in patients progressing on EGFR-tyrosine kinase inhibitors (TKIs). First-line afatinib is also effective in patients with central nervous system (CNS) metastasis. Here we report on outcomes of pretreated NSCLC patients with CNS metastasis who received afatinib within a compassionate use program. METHODS: Patients with NSCLC progressing after at least one line of chemotherapy and one line of EGFR-TKI treatment received afatinib. Medical history, patient demographics, EGFR mutational status, and adverse events including tumor progression were documented. RESULTS: From 2010 to 2013, 573 patients were enrolled and 541 treated with afatinib. One hundred patients (66% female; median age, 60 years) had brain metastases and/or leptomeningeal disease with 74% having documented EGFR mutation. Median time to treatment failure for patients with CNS metastasis was 3.6 months, and did not differ from a matched group of 100 patients without CNS metastasis. Thirty-five percent (11 of 31) of evaluable patients had a cerebral response, five (16%) responded exclusively in brain. Response duration (range) was 120 (21-395) days. Sixty-six percent (21 of 32) of patients had cerebral disease control on afatinib. Data from one patient with an impressive response showed an afatinib concentration in the cerebrospinal fluid of nearly 1 nMol. CONCLUSION: Afatinib appears to penetrate into the CNS with concentrations high enough to have clinical effect on CNS metastases. Afatinib may therefore be an effective treatment for heavily pretreated patients with EGFR-mutated or EGFR-TKI-sensitive NSCLC and CNS metastasis.

Signal transduction pathways as novel therapy targets in lung cancer.

Cytotoxic therapy for lung-cancer patients has only moderately improved during the last decades. Simultaneously, efforts of intensive research to increase our understanding of the molecular basis of lung cancer have been undertaken. The cancer cell has been characterised by several genetic changes that lead to altered cellular functions. In addition, multiple factors of the cancer-cell environment further affect the tumour cell via various receptors and subsequent signaling pathways. The increased knowledge of cellular signaling offers the opportunity to develop novel substances that target specific pathway molecules. In the current review, some of the most essential receptors and signaling pathways involved in lung cancer will be described. In conjunction, examples of novel target-specific agents that have already found their way into clinical trials will be discussed.

Non-small-cell lung cancer: multimodality approach in stage-III resectable disease.

The long-term results of surgery +/- radiotherapy in patients with operable disease of locally advanced non-small-cell lung cancer are discouraging. In the vast majority, disseminated microscopic disease, resulting in the later occurrence of distant metastases, contributes substantially to this poor long-term outcome. The further development of multimodality treatment approaches in randomised trials, including effective systemic therapy, is necessary. These approaches and the current status of multimodality treatment strategies of resectable locally advanced non-small-cell lung cancer are discussed.

Combined modality treatment for locally advanced non-small cell lung cancer: preoperative chemoradiation does not result in a poorer quality of life.

The German Lung Cancer Cooperative Group (GLCCG) is assessing the impact of chemoradiation in addition to chemotherapy in the neoadjuvant treatment of stage III NSCLC. After three cycles of cisplatin/etoposide patients receive either hyperfractionated radiotherapy (RT) with concurrent carboplatin/vindesine and then surgery (arm A) versus surgery and then conventional RT (arm B). Quality of life (QL) was assessed throughout therapy using the EORTC QLQ-C30 and EORTC QLQ-LC 13. Of 126 eligible patients, 54 completed treatment. For patients in both treatment arms physical functioning decreased, whereas dyspnoea, fatigue and pain increased from beginning to the end of treatment. For self-assessed QL no statistically significant effect was found in or between the two treatment arms. The combined modality approach with preoperative radio/chemotherapy proves to be feasible in treating locally advanced NSCLC patients without decreasing their subjective QL.

Preoperative chemotherapy with and without additional radiochemotherapy: benefit and risk for surgery of stage III non-small cell lung cancer.

OBJECTIVE: Multi-modality approaches are increasingly employed to improve prognosis in surgically treated stage III non-small cell lung cancer (NSCLC). Risk and benefit of the preoperative therapeutic chemotherapy or combined radiochemotherapy on surgical morbidity and mortality are still a matter of debate. METHODS: In 1995, a national phase III trial was started to compare (arm A) preoperative chemotherapy followed by twice-daily chemoradiation and consecutive surgery, with (arm B) preoperative chemotherapy alone followed by surgery and consecutive radiotherapy. An interim analysis with 277 patients was performed to assess surgical risk and complication rates. RESULTS: of the 358 patients, 273 (71%) underwent thoracotomy, 130 (73%) in arm A and 143 (69%) in arm B. Of the 273 patients undergoing thoracotomy, 168 had stage IIIB disease. Complete resection (R0) was achieved in 212 patients (78%), 104 in arm A (80%) and 108 in arm B (76%) (P=n.s.). There was no difference in the proportion of complex resections between treatment arms (41% in arm A; 48% in arm B). Whilst bronchial stump insufficiency (3.8 vs 2.1%) and bleeding requiring re-thoracotomy (1.5 vs 0.7%) prevailed slightly in arm A, the occurrence of pneumonia divided similar in both treatment arms (4.6 vs 4.9%). Surgical mortality reached 6.1% in arm A (8/130) and 5.6% in arm B(6/143) (P=n.s.). CONCLUSIONS: In both treatment arms, a similar percentage of patients could be forwarded to surgery, even in stage IIIB disease. Bimodality induction seems to be superior with regard to resection rates (R0) (n.s.), but was associated with a higher complication rate, especially bronchial stump insufficiency.