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Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma with a poor prognosis. Initial responses to standard-of-care chemo-immunotherapy are, unfortunately, followed by rapid disease recurrence in most patients. Current treatment options are limited, with no therapies specifically approved as third-line or beyond. Delta-like ligand 3 (DLL3), a Notch inhibitory ligand, is an attractive therapeutic target because it is overexpressed on the surface of SCLC cells with minimal to no expression on normal cells. Several DLL3-targeted therapies are being developed for the treatment of SCLC and other neuroendocrine carcinomas, including antibody-drug conjugates (ADCs), T-cell engager (TCE) molecules, and chimeric antigen receptor (CAR) therapies. First, we discuss the clinical experience with rovalpituzumab tesirine (Rova-T), a DLL3-targeting ADC, the development of which was halted due to a lack of efficacy in phase 3 studies, with a view to understanding the lessons that can be garnered for the rapidly evolving therapeutic landscape in SCLC. We then review preclinical and clinical data for several DLL3-targeting agents that are currently in development, including the TCE molecules—tarlatamab (formerly known as AMG 757), BI 764532, and HPN328—and the CAR T-cell therapy AMG 119. We conclude with a discussion of the future challenges and opportunities for DLL3-targeting therapies, including the utility of DLL3 as a biomarker for patient selection and disease progression, and the potential of rational combinatorial approaches that can enhance efficacy. [ABSTRACT FROM AUTHOR]

In CheckMate 9LA (NCT03215706), first-line nivolumab plus ipilimumab with chemotherapy (2 cycles) significantly improved overall survival versus chemotherapy (4 cycles) in patients with metastatic non-small cell lung cancer and no known sensitising epidermal growth factor receptor / anaplastic lymphoma kinase alterations. We present exploratory patient-reported outcomes (PROs; minimum follow-up, 2 years). In patients (N = 719) randomised 1:1 to nivolumab plus ipilimumab with chemotherapy or chemotherapy alone, disease-related symptom burden and health-related quality of life were assessed using the Lung Cancer Symptom Scale (LCSS) and 3-level EQ-5D (EQ-5D-3L). Treatment-phase changes in LCSS average symptom burden index (ASBI), LCSS three-item global index (3-IGI) and EQ-5D-3L visual analogue scale (VAS) and utility index (UI) over time were analysed descriptively and using mixed-effect model repeated measures. Time-to-deterioration/improvement analyses were conducted. Treatment-phase PRO questionnaire completion rates were >80%. Mean treatment-phase changes showed no deterioration from baseline in both arms for LCSS ASBI/3-IGI and EQ-5D-3L VAS/UI; however, minimally important differences were not met. Mixed-effect model repeated measures analyses showed overall reduction in symptom burden from baseline for both arms; changes from baseline for LCSS 3-IGI and EQ-5D-3L VAS/UI were numerically improved with nivolumab plus ipilimumab with chemotherapy versus chemotherapy, but minimally important differences were not met. Nivolumab plus ipilimumab with chemotherapy delayed time-to-definitive-deterioration versus chemotherapy (LCSS ASBI: hazard ratio, 0.62 [95% confidence interval, 0.45–0.87]); results were similar across PRO measures. At 2-year minimum follow-up, first-line nivolumab plus ipilimumab with chemotherapy reduced the risk of definitive deterioration in disease-related symptom burden and health-related quality of life versus chemotherapy and maintained QoL in patients with metastatic non-small cell lung cancer. Clinical trial registration: ClinicalTrials.gov Identifier, NCT03215706. • Patient-reported outcomes were assessed using the Lung Cancer Symptom Scale and EQ-5D in CheckMate 9LA. • Risk of symptom deterioration was lower with nivolumab + ipilimumab + chemo versus chemo. • 1L nivolumab + ipilimumab + chemo maintained quality of life in patients versus chemo. • Data confirm clinical benefit of 1L nivolumab + ipilimumab + chemo in metastatic non-small cell lung cancer. [ABSTRACT FROM AUTHOR]

The transcription factor NRF2 (nuclear factor E2-related factor 2) (also known as nuclear factor, erythroid 2 like 2 [NFE2L2]) is the master regulator of cellular antioxidant responses. NRF2 is repressed by interaction with a redox-sensitive protein KEAP1 (Kelch-like ECH-associated protein 1). Dysregulation of KEAP1/NRF2 transcriptional activity has been associated with the pathogenesis of multiple diseases, and the KEAP1/NRF2 axis has emerged to be the most important modulator of cellular homeostasis. Oxidative stress plays an important role in the initiation and progression of many chronic diseases, including diabetes, cancer, and neurodegenerative diseases. Although its role in immunotherapy is still somewhat controversial, it is well documented from clinical studies that KEAP1/NRF2 mutations in NSCLCs are associated with resistance to various cancer treatments including chemotherapy, X-irradiation, TKI treatment, and a shorter OS and currently available results from clinical trials suggest that KEAP1/NRF2 mutations can be used as a prognostic biomarker (poorer prognosis) for determining prognosis following immunotherapy and a predictive marker for chemo-, radio-, immunotherapy- and TKI-resistance. Despite overwhelming enthusiasm about the various KEAP1/NRF2 inhibitors that have been described during the last decades, none of these inhibitors are currently explored in clinical trials or in clinical applications which clearly add weight to the proposal that the development of these inhibitors remains challenging, but will be beneficial for novel treatment approaches in NSCLC in the near future. In this review we highlight the molecular features, the key components, and possible inhibitors of the KEAP1/NRF2 pathway, its role as prognostic and predictive biomarker, and the resulting clinical implications in NSCLC patients. [ABSTRACT FROM AUTHOR]

• Subgroup analysis of a non-interventional study in adenocarcinoma NSCLC. • Outcomes with nintedanib plus docetaxel after chemo- and immunotherapy (n = 67). • Nintedanib plus docetaxel given in third- or later-lines in 57 patients (85.1%). • Clinical effectiveness demonstrated: DCR was 78.2% and median OS was 8.8 months. • Provides real-world data to inform management in the changing treatment landscape. To evaluate the effectiveness and safety of nintedanib plus docetaxel in patients with advanced adenocarcinoma non-small cell lung cancer (NSCLC) previously treated with both chemo- and immunotherapy. LUME-BioNIS is a European, prospective, multicenter, non-interventional study of patients with advanced adenocarcinoma NSCLC, who initiated nintedanib plus docetaxel after first-line chemotherapy in routine practice according to the approved nintedanib EU label. The primary objective is to explore whether molecular biomarkers can predict overall survival (OS). Information on clinical or radiologic progression and death, and adverse drug reactions (ADRs)/fatal adverse events (AEs) was collected during follow-up. Here, we report a subgroup analysis evaluating outcomes in immunotherapy-pretreated patients. Of 260 enrolled patients, 67 (25.8%) had prior immunotherapy and were included in this subgroup analysis. Prior immunotherapy was administered in first-line in 20 patients (29.9%; combined with chemotherapy in 4 patients [6.0%]) and later-lines in 47 patients (70.1%), and most commonly comprised nivolumab (39 patients; 58.2%), atezolizumab (14 patients; 20.9%) and pembrolizumab (11 patients; 16.4%). Nintedanib plus docetaxel was given in second-line in 10 patients (14.9%) and in later-lines in 57 patients (85.1%). Median OS was 8.8 months (95% confidence interval [CI]: 7.0–11.5) and median progression-free survival (PFS) was 4.6 months (95% CI: 3.5–5.7). Among 55 patients with available data, rates of objective response and disease control were 18.2% and 78.2%, respectively. In 65 patients evaluable for safety, the most common on-treatment ADRs/AEs were malignant neoplasm progression (19 patients; 29.2%), diarrhea (21 patients; 32.3%) and nausea (10 patients; 15.4%). Used according to the approved nintedanib label in routine practice, nintedanib plus docetaxel demonstrated clinical effectiveness, with no unexpected safety findings, in patients with prior chemotherapy and first- or later-line immunotherapy. These data add to the real-world evidence that can inform clinical decisions in the changing therapeutic landscape. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

• SB8 and reference bevacizumab (BEV) were equivalent per the risk ratio of best ORR. • Survival outcomes further supported the biosimilarity between SB8 and BEV. • Safety, pharmacokinetics, and immunogenicity were comparable between SB8 and BEV. Efficacy, safety, pharmacokinetics (PK), and immunogenicity of the biosimilar candidate SB8 was compared to its reference product bevacizumab (BEV) in patients with metastatic or recurrent nonsquamous non―small cell lung cancer. Patients were randomized (1:1) in a phase III, double-blind study to receive intravenous SB8 or BEV 15 mg/kg with paclitaxel/carboplatin every 3 weeks for 24 weeks, followed by SB8 or BEV maintenance monotherapy. The primary endpoint was best overall response rate (ORR) by 24 weeks. Secondary endpoints included survival outcomes, safety, PK, and immunogenicity. 763 patients (SB8, n = 379; BEV, n = 384) were randomized; baseline characteristics were well balanced. Best ORR in the FAS was 47.6% and 42.8%, and best ORR in the PPS was 50.1% and 44.8% for SB8 and BEV, respectively. The risk ratio of best ORR was 1.11 (90% CI, 0.975−1.269), and the risk difference in best ORR was 5.3% (95% CI, −2.2%–12.9%). Median survival outcomes were comparable between SB8 and BEV: progression-free survival was 8.50 vs 7.90 months, respectively (HR [95% CI], 0.99 [0.83–1.18]; p = 0.9338); overall survival was 14.90 vs 15.80 months, respectively (HR [95% CI], 1.03 [0.83–1.28]; p = 0.7713); and duration of response was 7.70 vs 7.00 months, respectively (HR [95% CI], 1.05 [0.81–1.37]; p = 0.6928). Severity and incidence of treatment-emergent adverse events, PK, and immunogenicity were comparable between SB8 and BEV. This study demonstrated equivalence between SB8 and BEV in terms of best ORR risk ratio, with comparable safety, PK, and immunogenicity. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

• IO based regimens are the new frontline standard for advanced NSCLC with good PS. • Predictive biomarkers are needed to improve patients' selection and outcomes. • Trials are on-going to address resistance to PD-(L)1 and CTLA-4 inhibitors. The development of PD-1, PD-L1 and CTLA-4 immune checkpoint inhibitors (CPI) has revolutionised the treatment of advanced non-small cell lung cancer (NSCLC). The potential of immunotherapy (IO) to induce durable responses for a subset of patients represents a therapeutic milestone. After the approval of front-line single agent pembrolizumab, IO-based combinations are rapidly entering clinical practice resulting in a fast change of treatment algorithms for advanced NSCLC. We hereby summarize the recent first-line phase 3 trials evaluating PD-(L)1 blockade plus chemotherapy (ChT) and PD-1 plus CTLA-4 CPI for advanced NSCLC and provide potential treatment recommendations. [ABSTRACT FROM AUTHOR]

In the phase III CheckMate 227 study, first-line nivolumab + ipilimumab significantly prolonged progression-free survival (co-primary end-point) versus chemotherapy in patients with advanced non–small-cell lung cancer (NSCLC) and high tumour mutational burden (TMB; ≥10 mutations/megabase). To evaluate patient-reported outcomes (PROs) in this population. Disease-related symptoms and general health status were assessed using the validated PRO questionnaires Lung Cancer Symptom Scale (LCSS) and EQ-5D, respectively. LCSS average symptom burden index (ASBI) and three-item global index (3-IGI) and EQ-5D visual analogue scale (VAS) and utility index (UI) scores and changes from baseline were analysed descriptively. Longitudinal changes were assessed by mixed-effect model repeated measures (MMRMs) and time to first deterioration/improvement analyses. In the high TMB population, PRO questionnaire completion rates were ∼90% at baseline and >80% for most on-treatment assessments. During treatment, mean changes from baseline with nivolumab + ipilimumab showed early, clinically meaningful improvements in LCSS ASBI/3-IGI and EQ-5D VAS/UI; with chemotherapy, symptoms and health-related quality of life remained stable (LCSS ASBI/3-IGI, EQ-5D UI) or improved following induction (EQ-5D VAS). MMRM-assessed changes in symptom burden were improved with nivolumab + ipilimumab versus chemotherapy. Symptom deterioration by week 12 was lower with nivolumab + ipilimumab versus chemotherapy (22.3% versus 35.0%; absolute risk reduction: 12.7% [95% confidence interval 2.4–22.5]), irrespective of discontinuation. Time to first deterioration was delayed with nivolumab + ipilimumab versus chemotherapy across LCSS and EQ-5D summary measures. First-line nivolumab + ipilimumab demonstrated early, sustained improvements in PROs versus chemotherapy in patients with advanced NSCLC and high TMB. Clinical trial registration: NCT02477826. • Nivolumab + ipilimumab improved patient-reported outcomes versus chemotherapy in non–small-cell lung cancer. • Improvements were seen in lung cancer symptoms and in general health status. • Improvements with nivolumab + ipilimumab were rapid and durable. • Disease-related symptom deterioration was delayed with nivolumab + ipilimumab. [ABSTRACT FROM AUTHOR]

Abstract Background Nivolumab, a programmed death-1 inhibitor, prolonged overall survival and had a favourable safety profile versus docetaxel in previously treated patients with advanced non-squamous non-small cell lung cancer (NSCLC) in the phase III CheckMate 057 trial. Aim To evaluate health-related quality of life (HRQoL) using patient-reported outcomes. Methods Disease-related symptoms and general health status were assessed using two validated patient-reported instruments, the Lung Cancer Symptom Scale (LCSS) and the European Quality of Life Five Dimensions (EQ-5D), respectively. The proportion of patients with disease-related symptom improvement at 12 weeks on the LCSS average symptom burden index (ASBI) was a secondary end-point. LCSS 3-item global index (3-IGI), EQ-5D utility index and EQ-5D visual analogue scale (VAS) scores were also determined. Mixed-effects model repeated measures (MMRM) and time to first deterioration analyses assessed longitudinal changes. Results Mean baseline LCSS ASBI scores were similar in both arms. By week 12, rates of disease-related improvement (95% confidence interval) were similar between nivolumab (17.8% [13.6–22.7]) and docetaxel (19.7% [15.2–24.7]); however, numerical differences in LCSS ASBI mean change from baseline favoured nivolumab. Subsequently, LCSS ASBI scores improved with nivolumab and worsened with docetaxel, with statistically significant between-arm differences at weeks 12, 24, 30 and 42. HRQoL improvements with nivolumab versus docetaxel were also supported by the LCSS 3-IGI, EQ-5D VAS and MMRM analysis. Time to first HRQoL deterioration was longer with nivolumab than with docetaxel. Conclusion Nivolumab improved disease-related symptoms and overall health status versus docetaxel for second-line treatment of advanced non-squamous NSCLC. Clinical trial registration NCT01673867. Highlights • Nivolumab provided improvements in health-related quality of life in CheckMate 057. • Docetaxel was associated with stable or worsening of quality of life. • Disease-related deterioration was delayed with nivolumab versus docetaxel. [ABSTRACT FROM AUTHOR]

Background: Nintedanib in combination with docetaxel is approved in the European Union and other countries for the treatment of patients with advanced non-small-cell lung cancer (NSCLC) of adenocarcinoma histology after first-line chemotherapy, based on the overall survival findings of Phase III LUME-Lung 1 study. Change in target lesion size over time as a treatment effect was assessed in patients from this study. Methods: Tumor size was evaluated using predefined tumor measurements. Mixed-effects models were used to quantify individual relationships between time from randomization and tumor burden, measured as the sum of longest diameter (SLD) of target lesions and assessed by an independent review (Response Evaluation Criteria In Solid Tumors [RECIST] v1.0). Exploratory analyses were conducted on the overall adenocarcinoma population, adenocarcinoma patients with time from start of first-line therapy <9 months (TSFLT <9), adenocarcinoma patients who had progressive disease as best response to first-line therapy (PD-FLT), and in squamous cell carcinoma patients. Results: Estimated mean baseline SLD was 82.5 mm in the adenocarcinoma (n=658), 88.3 mm in the TSFLT <9 (n=405), 98.1 mm in the PD-FLT (n=117), and 94.3 mm in the squamous cell carcinoma (n=555) populations. Treatment with nintedanib/docetaxel showed a significant reduction in tumor size over time (P<0.0001) in patients with adenocarcinoma compared with placebo/docetaxel, and in patients with squamous cell carcinoma (P=0.0049). Treatment difference at 6 months was 9.7 mm in the overall adenocarcinoma population, 16.8 mm in the TSFLT <9 population, 19.7 mm in the PD-FLT population, and 6.8 mm in the squamous cell carcinoma population. SLD at 2 months post-randomization was identified as a surrogate endpoint for overall survival, in addition to progression-free survival, for all except the PD-FLT population. Conclusion: Treatment with nintedanib/docetaxel significantly decreased tumor burden and decelerated tumor size over time compared with placebo/docetaxel in the overall adenocarcinoma population, including in patients with the poorest prognosis due to aggressive tumor dynamics. [ABSTRACT FROM AUTHOR]

• Immunotherapy ± chemotherapy is a first-line treatment of choice in advanced NSCLC. • There is a major unmet need for treatment options after immunotherapy. • Targeting VEGF-promoted angiogenesis may reduce immunosuppression. • Anti-angiogenics may reinstate and enhance the effect of subsequent therapies. • Nintedanib, ramucirumab and other anti-angiogenics show promise after immunotherapy. The implementation of immune checkpoint inhibitors (ICIs), with or without chemotherapy, as first-line treatment for patients who do not have actionable mutations has proved to be a major paradigm shift in the management of advanced non-small cell lung cancer (NSCLC). However, the transition of ICIs, such as pembrolizumab and nivolumab, to a first-line setting has left an unmet need for effective second-line treatment options, which is an area of intense research. In 2020, we reviewed the biological and mechanistic rationale for anti-angiogenic agents in combination with, or following, immunotherapy with the aim of eliciting a so called 'angio-immunogenic' switch in the tumor microenvironment. Here, we review the latest clinical evidence of the benefits of incorporating anti-angiogenic agents into treatment regimens. While there is a paucity of prospective data, several recent observational studies indicate that the marketed anti-angiogenic drugs, nintedanib or ramucirumab, are effective in combination with docetaxel following immuno-chemotherapy. Addition of anti-angiogenics, like bevacizumab, have also demonstrated clinical benefit when combined with first-line immuno-chemotherapy regimens. Ongoing clinical trials are assessing these agents in combination with ICIs, with encouraging early results (e.g., ramucirumab plus pembrolizumab in LUNG-MAP S1800A). Also, several emerging anti-angiogenic agents combined with ICIs are currently being assessed in phase III trials following immunotherapy, including lenvatinib (LEAP-008), and sitravatinib (SAPPHIRE) It is hoped that these trials will help expand second-line treatment options in patients with NSCLC. Areas of focus in the future will include further molecular dissection of the mechanisms of resistance to immunotherapy and the various response–progression profiles to immunotherapy observed in the clinic and the monitoring of the dynamics of immunomodulation over the course of treatment. Improved understanding of these phenomena may help identify clinical biomarkers and inform the optimal use of anti-angiogenics in the treatment of individual patients. [ABSTRACT FROM AUTHOR]

A majority of patients with advanced or metastatic non-small cell lung cancer (NSCLC) will experience disease progression after first-line therapy. Patients who have advanced NSCLC that is especially aggressive, which is defined as disease that rapidly progresses on first-line treatment or disease that is refractory to first-line treatment, have a critical unmet medical need. These patients have a poor prognosis in the second-line setting. Several studies have recently shown that treatment with an antiangiogenic therapy may benefit these patients. This review summarizes the approved antiangiogenic therapies for the treatment of patients with advanced NSCLC in the second-line setting, specifically focusing on the outcomes from subgroups of patients with rapidly progressing or refractory disease. Several antiangiogenic agents, as monotherapy or in combination with other treatments, have been or are currently being studied in patients with advanced NSCLC. Antiangiogenics that are approved for use in patients with advanced NSCLC are limited to bevacizumab in combination with chemotherapy (nonsquamous NSCLC), ramucirumab in combination with docetaxel (all histologies), and nintedanib in combination with docetaxel (adenocarcinoma histology). This review focuses on the efficacy, safety, and quality of life outcomes in the subpopulation of patients with rapidly progressing or refractory NSCLC treated with approved antiangiogenic therapies in the second-line setting. We also discuss the impact of newly approved immunotherapy agents on the outcomes of patients with aggressive or refractory disease. Studies in progress and planned future research will determine if combination treatment with antiangiogenics and immunotherapies will benefit patients with aggressive, advanced NSCLC. [ABSTRACT FROM AUTHOR]

Objectives The REVEL study demonstrated improved efficacy for patients with advanced non-small cell lung cancer treated with ramucirumab plus docetaxel, independent of histology. This exploratory analysis characterized the treatment effect in REVEL patients who were refractory to prior first-line treatment. Materials and methods Refractory patients had a best response of progressive disease to first-line treatment. Endpoints included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), quality of life (QoL), and safety. Kaplan-Meier and Cox proportional hazards regression were performed for OS and PFS, and Cochran-Mantel-Haenszel test was used for response. QoL was assessed with the Lung Cancer Symptom Scale. Sensitivity analyses were performed on subgroups of the intent-to-treat population with limited time on first-line therapy. Results Of 1253 randomized patients in REVEL, 360 (29%) were refractory to first-line treatment. Baseline characteristics were largely balanced between treatment arms. In the control arm, median OS for refractory patients was 6.3 versus 10.3 months for patients not meeting this criterion, demonstrating the poor prognosis of refractory patients. Median OS (8.3 vs. 6.3 months; HR, 0.86; 95% CI, 0.68–1.08), median PFS (4.0 vs. 2.5 months; HR, 0.71; 95% CI, 0.57–0.88), and ORR (22.5% vs. 12.6%) were improved in refractory patients treated with ramucirumab compared to placebo, without new safety concerns or further deteriorating patient QoL. Conclusions The effect of ramucirumab in refractory patients is similar to that in the intent-to-treat population. The benefit/risk profile for refractory patients suggests that ramucirumab plus docetaxel is an appropriate treatment option even in this difficult-to-treat population. [ABSTRACT FROM AUTHOR]

The article focuses on the aspects of the treatment and precision diagnosis of advance non-small-cell lung cancer (NSCLC). Topics discussed include the importance of the pathological features of the cancer on determining the treatment options, the staging of the lung cancer based on the correct tumor-node-metastasis (TNM), and several treatment options for NSCLC such as platinum-based chemotherapy.

Background: Pembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) that has antitumor activity in advanced non-small-cell lung cancer (NSCLC), with increased activity in tumors that express programmed death ligand 1 (PD-L1).Methods: In this open-label, phase 3 trial, we randomly assigned 305 patients who had previously untreated advanced NSCLC with PD-L1 expression on at least 50% of tumor cells and no sensitizing mutation of the epidermal growth factor receptor gene or translocation of the anaplastic lymphoma kinase gene to receive either pembrolizumab (at a fixed dose of 200 mg every 3 weeks) or the investigator's choice of platinum-based chemotherapy. Crossover from the chemotherapy group to the pembrolizumab group was permitted in the event of disease progression. The primary end point, progression-free survival, was assessed by means of blinded, independent, central radiologic review. Secondary end points were overall survival, objective response rate, and safety.Results: Median progression-free survival was 10.3 months (95% confidence interval [CI], 6.7 to not reached) in the pembrolizumab group versus 6.0 months (95% CI, 4.2 to 6.2) in the chemotherapy group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.37 to 0.68; P<0.001). The estimated rate of overall survival at 6 months was 80.2% in the pembrolizumab group versus 72.4% in the chemotherapy group (hazard ratio for death, 0.60; 95% CI, 0.41 to 0.89; P=0.005). The response rate was higher in the pembrolizumab group than in the chemotherapy group (44.8% vs. 27.8%), the median duration of response was longer (not reached [range, 1.9+ to 14.5+ months] vs. 6.3 months [range, 2.1+ to 12.6+]), and treatment-related adverse events of any grade were less frequent (occurring in 73.4% vs. 90.0% of patients), as were grade 3, 4, or 5 treatment-related adverse events (26.6% vs. 53.3%).Conclusions: In patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells, pembrolizumab was associated with significantly longer progression-free and overall survival and with fewer adverse events than was platinum-based chemotherapy. (Funded by Merck; KEYNOTE-024 ClinicalTrials.gov number, NCT02142738 .). [ABSTRACT FROM AUTHOR]

Background: In the SQUIRE study, adding the anti-epidermal growth factor receptor (EGFR) IgG1 antibody necitumumab to first-line gemcitabine and cisplatin (GC + N) in advanced squamous non-small-cell lung cancer (sqNSCLC) significantly improved overall survival (OS); the safety profile was acceptable. We explored data for the German subpopulation (N = 96) of SQUIRE patients with EGFR-expressing tumors. Patient and Methods: Patients with stage IV sqNSCLC were randomized 1: 1 to up to 6 cycles of open-label GC + N or GC alone. GC + N patients with no progression continued on necitumumab monotherapy until disease progression or intolerable toxicity. The primary endpoint was OS; the secondary endpoints included progression-free survival (PFS), safety and health-related quality of life (EQ-5D, Lung Cancer Symptom Scale (LCSS)). Results: The 96 German SQUIRE patients with EGFR-expressing tumors (GC + N 42, GC 54) received a median of 4 GC cycles; the GC + N patients received 5 cycles of necitumumab. Adding necitumumab was associated with 41% risk reduction of death (hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.37-0.94, p = 0.026) and 44% risk reduction of progression (HR 0.56, 95% CI 0.33-0.95, p = 0.029). Adverse events typically associated with EGFR antibody treatment (including rash, hypomagnesemia) were more common with GC + N. The time to deterioration of the EQ-5D and LCSS scores showed no notable differences between the treatment arms, except for appetite loss (delayed for GC + N). Conclusion: The survival benefit from adding necitumumab to first-line GC was more pronounced in the German SQUIRE subpopulation with EGFR-expressing tumors than in the overall (intentionto- treat) population; toxicity was manageable and consistent with the overall population. [ABSTRACT FROM AUTHOR]

Immune evasion is recognized as a key strategy for cancer survival and progression. Hence, various approaches to restore antitumor immune responses are currently being investigated. In particular, agents targeting immune checkpoints, such as the cytotoxic T-lymphocyteassociated antigen-4 receptor and programmed death-1 receptor, have shown potential for improving tumor responses and survival in lung cancer patients. With the first immunomodulating agents having been approved for treatment of selected lung cancer patients, there are high expectations that treatment outcomes may be improved with the incorporation of immunotherapies into the various treatment cascades. [ABSTRACT FROM AUTHOR]

Objectives LUME-Lung 1 was a randomized, placebo-controlled, Phase III trial investigating nintedanib + docetaxel versus placebo + docetaxel in patients with advanced NSCLC progressing after first-line chemotherapy. Progression-free survival was significantly improved with nintedanib + docetaxel in the overall population and overall survival was significantly improved in the pre-specified analysis of patients with adenocarcinoma. We evaluated the frequency of characteristic adverse events (AEs) commonly seen with existing anti-angiogenic agents. Materials and methods The incidence and intensity of AEs were evaluated in all patients who received at least one dose of study medication ( N = 1307) and for the two main histologies: adenocarcinoma ( n = 653) and squamous cell carcinoma (SCC; n = 553). AEs of special interest were analyzed by category, preferred term, and worst CTCAE grade and included perforation, hypertension, bleeding, thromboembolic events, and skin disorders. Results and conclusion The incidence of patients with all-grade gastrointestinal (GI) perforations was low and balanced between arms (0.5% in both) and across histologies; the incidence of non-GI perforations was 1.2% with nintedanib + docetaxel versus 0.2% with placebo + docetaxel. The incidence of some events was higher with nintedanib + docetaxel versus placebo + docetaxel; hypertension (3.5% vs 0.9%), rash (11.0% vs 8.1%), and cutaneous adverse reactions (13.0% vs 10.7%). Rash and cutaneous adverse reactions were predominantly Grade 1–2 with both treatments. The incidence of all-grade bleeding was also slightly higher in nintedanib + docetaxel-treated patients (14.1% vs 11.6%) driven by between-treatment differences in the SCC subpopulation; most events were Grade 1–2. The proportion of patients with a thromboembolic event was low and comparable between arms for all grades (5.1% vs 4.6%) and Grade ≥3 (2.1% vs 3.1%). Safety evaluation of the LUME-Lung 1 study showed that the frequency of AEs commonly associated with other anti-angiogenic agents was lower with nintedanib + docetaxel. Survival benefits from addition of nintedanib to docetaxel in patients with adenocarcinoma after first-line therapy can be achieved alongside a manageable safety profile. [ABSTRACT FROM AUTHOR]

Objectives ABIGAIL, a phase II, randomized, open-label, multicenter study evaluated the correlation between biomarkers and best overall response (BOR) to bevacizumab with chemotherapy in patients with advanced or recurrent non-small-cell lung cancer (NSCLC). Exploratory analyses of vascular endothelial growth factor (VEGF) clinical genotyping data are presented. Materials and methods A total of 303 patients with NSCLC were randomized to receive bevacizumab 7.5 mg/kg or 15 mg/kg until progression or unacceptable toxicity (plus six cycles of chemotherapy). Patients provided blood samples for biomarker analysis. Exploratory analyses were conducted to assess whether genetic variants in VEGF-A or VEGFR-1/-2 act as efficacy or safety biomarkers. Single nucleotide polymorphisms (SNPs) were determined using individual genotyping assays. DNA analysis for 12 SNPs across three genes is reported: VEGF-A (five SNPs), VEGFR-1 (three SNPs), and VEGFR-2 (four SNPs). Results VEGF-A: c.+405/c.−634 (CG), VEGF-A: c.−460 >C; c−1498 >C (CT), and VEGF-A: c.−2578 C>A were associated with >50% higher odds of responding to treatment. VEGFR-1: rs9554316 (GT) was associated with >30% higher risk of progression and >40% higher risk of death. VEGF-A: c.+936 C>T was associated with higher incidence of hypertension. Conclusions Four genetic variants of VEGF-A and VEGFR-1 were associated with bevacizumab treatment outcome. Three variants in VEGF-A were associated with increased BOR, one variant in VEGFR-1 was associated with worse progression-free survival/overall survival. These associations were not statistically significant after correction for multiple testing. No genetic variant was associated with significantly higher risk of hypertension. Replication in additional studies may provide insight into the use of these variants to predict response to bevacizumab. [ABSTRACT FROM AUTHOR]

Summary: Background: The phase 3 LUME-Lung 1 study assessed the efficacy and safety of docetaxel plus nintedanib as second-line therapy for non-small-cell lung cancer (NSCLC). Methods: Patients from 211 centres in 27 countries with stage IIIB/IV recurrent NSCLC progressing after first-line chemotherapy, stratified by ECOG performance status, previous bevacizumab treatment, histology, and presence of brain metastases, were allocated (by computer-generated sequence through an interactive third-party system, in 1:1 ratio), to receive docetaxel 75 mg/m2 by intravenous infusion on day 1 plus either nintedanib 200 mg orally twice daily or matching placebo on days 2–21, every 3 weeks until unacceptable adverse events or disease progression. Investigators and patients were masked to assignment. The primary endpoint was progression-free survival (PFS) by independent central review, analysed by intention to treat after 714 events in all patients. The key secondary endpoint was overall survival, analysed by intention to treat after 1121 events had occurred, in a prespecified stepwise order: first in patients with adenocarcinoma who progressed within 9 months after start of first-line therapy, then in all patients with adenocarcinoma, then in all patients. This trial is registered with ClinicalTrials.gov, number NCT00805194. Findings: Between Dec 23, 2008, and Feb 9, 2011, 655 patients were randomly assigned to receive docetaxel plus nintedanib and 659 to receive docetaxel plus placebo. The primary analysis was done after a median follow-up of 7·1 months (IQR 3·8–11·0). PFS was significantly improved in the docetaxel plus nintedanib group compared with the docetaxel plus placebo group (median 3·4 months [95% CI 2·9–3·9] vs 2·7 months [2·6–2·8]; hazard ratio [HR] 0·79 [95% CI 0·68–0·92], p=0·0019). After a median follow-up of 31·7 months (IQR 27·8–36·1), overall survival was significantly improved for patients with adenocarcinoma histology who progressed within 9 months after start of first-line treatment in the docetaxel plus nintedanib group (206 patients) compared with those in the docetaxel plus placebo group (199 patients; median 10·9 months [95% CI 8·5–12·6] vs 7·9 months [6·7–9·1]; HR 0·75 [95% CI 0·60–0·92], p=0·0073). Similar results were noted for all patients with adenocarcinoma histology (322 patients in the docetaxel plus nintedanib group and 336 in the docetaxel plus placebo group; median overall survival 12·6 months [95% CI 10·6–15·1] vs 10·3 months [95% CI 8·6–12·2]; HR 0·83 [95% CI 0·70–0·99], p=0·0359), but not in the total study population (median 10·1 months [95% CI 8·8–11·2] vs 9·1 months [8·4–10·4]; HR 0·94, 95% CI 0·83–1·05, p=0·2720). Grade 3 or worse adverse events that were more common in the docetaxel plus nintedanib group than in the docetaxel plus placebo group were diarrhoea (43 [6·6%] of 652 vs 17 [2·6%] of 655), reversible increases in alanine aminotransferase (51 [7·8%] vs six [0·9%]), and reversible increases in aspartate aminotransferase (22 [3·4%] vs three [0·5%]). 35 patients in the docetaxel plus nintedanib group and 25 in the docetaxel plus placebo group died of adverse events possibly unrelated to disease progression; the most common of these events were sepsis (five with docetaxel plus nintedanib vs one with docetaxel plus placebo), pneumonia (two vs seven), respiratory failure (four vs none), and pulmonary embolism (none vs three). Interpretation: Nintedanib in combination with docetaxel is an effective second-line option for patients with advanced NSCLC previously treated with one line of platinum-based therapy, especially for patients with adenocarcinoma. Funding: Boehringer Ingelheim. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Tigatuzumab, a humanized monoclonal DR5 agonist antibody induces apoptosis in human cancer cell lines. The objective of this study was to investigate the antitumor effects of tigatuzumab combined with carboplatin/paclitaxel in chemotherapy-naïve patients with metastatic/unresectable non-small cell lung cancer (NSCLC). Methods: Patients with histologically or cytologically confirmed NSCLC stage IIIB/IV disease by RECIST (version 1.0) and ECOG-PS 0–1 were enrolled at 15 European sites. Patients received tigatuzumab or placebo intravenously with carboplatin/paclitaxel every 3 weeks (1 cycle) for up to 6 cycles. The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), objective response rate and safety. Results: 97 patients were analyzed for efficacy (49 tigatuzumab; 48 placebo). Median PFS (95% CI) was 5.4 months (3.3, 6.6) for tigatuzumab compared with 4.3 months (4.1, 5.8) for placebo. Median OS (95% CI) was 8.4 months (6.9, 16.3) for tigatuzumab versus 9.0 months (7.6, 14.5) for placebo. 12 patients (24.5%) in the tigatuzumab arm and 11 patients (22.9%) in the placebo arm had partial response. No patient had complete response. In a prospectively-defined Fc gamma receptor genotype subset (n =25), there was a non-significant trend toward increased PFS with tigatuzumab versus placebo (HR=0.47; 95% CI: 0.16, 1.35) but no difference in OS. Tigatuzumab was well tolerated. However, grade 3/4 neutropenia was reported in 10 patients (20.4%) receiving tigatuzumab compared with 4 patients (8.3%) receiving placebo. Conclusions: Tigatuzumab was well tolerated but did not improve efficacy of carboplatin/paclitaxel in systemic therapy-naïve, unselected advanced NSCLC patients. Clinical trials identifier: NCT00991796. [Copyright &y& Elsevier]

Non-small-cell lung cancer is one of the leading causes of deaths from cancer worldwide. Therefore, improvements in diagnostics and treatments are urgently needed. In this review, we will discuss the evolution of lung cancer staging towards more non-invasive, endoscopy-based, and image-based methods, and the development of stage-adapted treatment. A special focus will be placed on the role of novel surgical approaches and modern radiotherapy strategies for early stages of disease, the effect of multimodal treatment in locally advanced disease, and ongoing developments in the treatment of patients with metastatic disease. In particular, we will include an emphasis on targeted therapies, which are based on the assumption that a treatable driver mutation or gene rearrangement is present within the tumour. Finally, the position of lung cancer treatment on the pathway to personalised therapy will be discussed. [ABSTRACT FROM AUTHOR]

Abstract: Background: Small cell lung cancer (SCLC) is associated with poor prognosis due to its early metastatic potential and lack of improved outcomes with newer cytotoxic agents. Identifying factors associated with clinical outcomes can help clinicians determine which patients are more likely to benefit from therapy. Functional Assessment of Cancer Therapy (FACT) subscales and Eastern Cooperative Oncology Group performance status (ECOG PS) were retrospectively analyzed as prognostic factors for overall survival (OS) and progression-free survival (PFS) in patients with extensive-stage disease (ED)-SCLC. Methods: Using data from a Phase III trial of pemetrexed–carboplatin vs. etoposide–carboplatin, the effect of the prognostic factors on OS and PFS was analyzed via Cox models. The Kaplan–Meier method was used to estimate OS and PFS parameters for the prognostic subgroups (defined by baseline FACT scores and ECOG PS). Results: Patients with higher baseline FACT-General (FACT-G) score (≥median) had significantly higher OS (hazard ratio [HR]=0.62, P <.0001) and PFS (HR=0.83, P =.032) compared with patients with lower FACT-G score (

We investigated the relationship between plasma protein biomarker concentrations and clinical outcomes in 52 patients with relapsed/refractory advanced non-small cell lung cancer (NSCLC) treated with 400~mg bid sorafenib in a phase II trial. Blood samples were collected at baseline, on day 15 of cycle 1 (C1D15), and on day 1 of cycle 3 (C3D1), and plasma concentrations of total VEGF, VEGF-165, soluble (s) VEGFR-2, PDGF-BB, sPDGFR-β, sEGFR, sHER-2, uPA, PAI-1, uPAR, TIMP-1, and circulating Ras p21 were assayed by ELISA. Elevated baseline VEGF, VEGF-165, PDGF-BB, Ras p21, and TIMP-1 concentrations were associated with poorer patient outcomes (shorter overall survival [OS] and/or progression-free survival [PFS]). During treatment, the mean concentrations of sVEGFR-2, PDGF-BB, sPDGFR-β, TIMP-1, uPAR, and PAI-1 decreased, while the mean sEGFR concentration increased. Increases in VEGF, VEGF-165, PDGF-BB, and TIMP-1 during treatment were associated with better outcomes (longer OS and/or PFS), whereas increases in plasma Ras p21 during treatment were associated with shorter PFS. The associations between baseline concentrations and/or pharmacodynamic changes in plasma proteins and clinical outcomes in NSCLC patients treated with sorafenib suggest that these biomarkers may have a prognostic role and/or predict the efficacy of sorafenib in patients with NSCLC. [ABSTRACT FROM AUTHOR]

Abstract: Lung cancer continues to present an enormous global burden of morbidity and mortality, despite an increasing therapeutic armamentarium of chemotherapy and targeted agents. Recent research efforts have been directed towards identifying predictors of response to treatment, in order to facilitate the selection of patients likely to obtain the greatest benefit from specific therapeutic interventions, with the ultimate goal of providing customized therapy. A strong scientific basis exists for the use of markers to identify patients who are most likely to respond to biological and targeted therapies, based on characteristics such as tumour genotype and histology. Biomarkers have the potential to aid in patient stratification (risk assessment), treatment-response identification (surrogate markers), or differential diagnosis (identifying individuals who are likely to respond well to specific therapies). Numerous trials have demonstrated correlations between molecular biomarkers and the outcome of treatment with targeted therapies such as epidermal growth factor inhibitor tyrosine-kinase inhibitors in patients with non-small-cell lung cancer (NSCLC). The recently completed MarkER Identification Trial (MERIT) found some evidence of a link between the molecular profile of a tumour and the clinical response to erlotinib in patients with relapsed NSCLC. However, MERIT also highlighted the difficulties in obtaining adequate samples for the various procedures involved in genetic analyses in clinical trials. Routine clinical practice brings its own challenges relating to biopsy techniques and tissue availability and this has implications for the application of molecular analyses in treatment decision-making. Applying the lessons learned from tissue sampling and molecular testing in MERIT and other major NSCLC trials will be essential in paving the way for the routine use of biomarker analyses in clinical practice. [Copyright &y& Elsevier]

Abstract: Purpose: To determine the maximum tolerated dose (MTD) of sunitinib plus gemcitabine/cisplatin for first-line treatment of patients with advanced non-small cell lung cancer (NSCLC). Safety, pharmacokinetics, and antitumor activities were evaluated. Methods: Patients ≥18 years with Eastern Cooperative Oncology Group performance status 0/1 and stage IIIB/IV NSCLC were included in this open-label, multicenter, dose-escalation phase I study. Treatment was administered in 3-week cycles: oral sunitinib 37.5 or 50mg/day intermittently (Schedule 2/1: 2 weeks on treatment, 1 week off treatment) or 25mg continuous daily dosing (CDD) schedule with intravenous infusions of gemcitabine (1000 or 1250mg/m2 days 1, 8) and cisplatin (80mg/m2 day 1). Results: A total of 28 evaluable patients were assigned to four dose levels. Most adverse events (AEs) on the Schedule 2/1 MTD were mild to moderate. Dose delays due to myelosuppression occurred on both schedules, limiting treatment to a median of four cycles. Four of 18 evaluable patients (22%) on Schedule 2/1 and 1 of 6 patients (17%) on the CDD schedule had confirmed partial responses. Conclusions: The MTD was identified as sunitinib 37.5mg (Schedule 2/1), gemcitabine 1250mg/m2, and cisplatin 80mg/m2, with most AEs being mild to moderate. However, frequent dose delays due to myelosuppression occurred. There was evidence of antitumor activity with this combination. [ABSTRACT FROM AUTHOR]

Abstract: This single-arm phase II study evaluated the tumor-vascular disrupting agent ASA404 (vadimezan, 5,6-dimethylxanthenone-4-acetic acid/DMXAA) 1800mg/m2 plus standard therapy of carboplatin and paclitaxel in patients with advanced non-small cell lung cancer (NSCLC). This ASA404 dose is 50% higher than that used in previous phase II studies. Thirty patients with histologically confirmed stage IIIb or IV NSCLC previously untreated with chemotherapy received carboplatin AUC 6mg/mlmin plus paclitaxel 175mg/m2 plus ASA404 1800mg/m2 every 21 days for up to six cycles. The addition of ASA404 1800mg/m2 to standard therapy produced little change in the systemic exposure of either total or free carboplatin or paclitaxel, and was generally well-tolerated, with no cardiac serious adverse events or clinically relevant ophthalmic abnormalities. The best overall tumor response was partial response, which was seen in 37.9% of patients by independent assessment and in 46.7% by investigator assessment. Stable disease was seen in 48.3% of patients by independent assessment and in 43.3% by investigator assessment. Median time to tumor progression was 5.5 months by investigator assessment and median survival was 14.9 months. The data from this trial corroborate findings from a recent randomized phase II trial, which suggested improvements in efficacy variables, including survival, when ASA404 1200mg/m2 was added to standard therapy for advanced NSCLC. The manageable safety profile, lack of adverse pharmacokinetic interactions and efficacy outcomes seen in this single-arm study suggest that ASA404 1800mg/m2 is a viable dose for future combination studies. [Copyright &y& Elsevier]

Abstract: Introduction: This phase II study assessed the efficacy and safety of oral vinorelbine given weekly in combination with carboplatin (CBDCA) AUC 5 once every 3 weeks for four cycles in chemonaive patients with advanced non-small cell lung carcinoma (NSCLC), followed by consolidation therapy with single-agent oral vinorelbine in non-progressive patients. Methods: Chemonaive advanced NSCLC patients received four cycles of combination therapy with CBDCA AUC 5 day 1 and oral vinorelbine, 60mg/m2 on days 1, 8 and 15 (cycle 1), dose increased to 80mg/m2 (cycles 2–4) in absence of grades 3–4 neutropenia (NCI-CTCv2). Consolidation therapy with oral vinorelbine was continued (cycle 5) at same dosage; if dose was decreased during combination therapy, it was given at 60mg/m2, then increased at 80mg/m2 (cycle 6) in absence of grades 3–4 neutropenia until PD, toxicity or patient''s refusal. Results: A total of 57 patients were registered and 56 patients were treated (ITT population), median age was 61 years (37–71). Objective response evaluated by RECIST was 17.9% (95% confidence interval, CI [8.9–30.4]) and disease control (CR, PR, NC) 73.2% (95% CI [59.7–84.2]), median progression-free survival 4.3 months (95% CI [3.1–5.1]) with median overall survival 9.7 months (95% CI [7.7–11.9]) and 1-year survival 37.1% (95% CI [24.4, 49.9]). Grades 3–4 neutropenia occurred in 67.9% of patients during combination and 20% during consolidation; febrile neutropenia occurred in 4 patients (7.1%) during combination therapy. Non-hematological toxicities occurred primarily during combination (grade 3 nausea and grade 3 vomiting in 7.1% of patients). Conclusions: The combination of oral vinorelbine given weekly in 3-week cycles in combination with carboplatin followed by consolidation therapy with oral vinorelbine as a single-agent was able to achieve efficacy results in line with other doublets including carboplatin in terms of response as well as survival. This regimen reported a good profile of tolerability in the treatment of advanced NSCLC, allowing that this combination can be easily proposed for the palliative care of NSCLC patients where the advantages of carboplatin over cisplatin are still appreciated. [Copyright &y& Elsevier]

Summary: Chemotherapy has reached a therapeutic plateau in the treatment of advanced non-small cell lung cancer (NSCLC), and effective, better-tolerated treatment strategies are needed. An improved understanding of the molecular processes underlying tumor biology has led to the development of therapies that target these processes. Intracellular signaling pathways related to the vascular endothelial growth factor and the epidermal growth factor receptor both play a central role in tumorigenesis as well as tumor growth, and are therefore rational targets for anti-cancer drug development. Various agents that target these pathways are in clinical development. Some of these have already changed treatment practice in NSCLC, most notably the monoclonal antibody, bevacizumab, in combination with chemotherapy in the first-line setting and the small-molecule tyrosine-kinase inhibitors, erlotinib and gefitinib, in the second-line setting. We will review the clinical data for various novel therapies and identify how these agents are improving outcomes in the first- and second-line treatment of advanced NSCLC. [Copyright &y& Elsevier]

Summary: Purpose: Based on the promising activity of paclitaxel in small-cell lung cancer (SCLC) we conducted a randomized phase III trial to evaluate whether a combination of paclitaxel, carboplatin and etoposide phosphate (TEC) improves survival and time to progression as well as tolerability and quality of life (QoL) compared to a regimen of carboplatin, etoposide phosphate and vincristine (CEV) in SCLC patients. Patients and methods: Six hundred and fourteen patients with stages I–IV SCLC were randomly assigned between January 1998 and December 1999 to both treatment arms. All patients were evaluated for response rate, survival, side effects and quality of life with overall survival (OS) serving as primary endpoint. A final analysis was done after a six-year follow-up. Survival curves were estimated using Kaplan–Meier curves and tested with the log-rank test. Quality of life data were assessed in using the EORTC QLQ-C30 questionnaire and evaluated by calculating and comparing the mean scores as well as applying longitudinal techniques. Results: Six hundred and eight patients were evaluable for efficacy and toxicity. The long-term follow-up confirms the significant survival benefit for the paclitaxel, etoposide, carboplatin (TEC) regimen with a median OS of 12.5 months compared to 11.7 months for the CEV arm (HR, 1.21; 95% CI, 1.02–1.43; P =.030). The 5-year survival rates were 14% for the experimental versus 6 % for the CEV arm. Significant survival prolongation was also observed in the subgroup of patients with stage IV disease (HR, 1.27; 95% CI, 1.00–1.60; P =.047). The previously reported clinical benefit in form of an overall reduction of grade 3/4 toxicity was backed by the results of the comprehensive QoL analysis we report hereby. TEC significantly improves the relevant QoL parameters like global overall QoL or physical functioning. Conclusion: When administered in combination with etoposide and carboplatin, paclitaxel is able to offer in SCLC patients with extensive disease a survival benefit without additional toxicities, but with gains in patient-reported quality of life. In terms of efficient palliative care, TEC might be seen as an alternative to standard cisplatin plus etoposide in patients requesting a powerful palliative regimen not compromising any survival benefit. [Copyright &y& Elsevier]

Summary: Background:: Gefitinib is the first approved EGFR tyrosine-kinase inhibitor indicated for the treatment of patients with locally advanced (IIIB) or metastatic NSCLC after failure of platinum-based first-line therapy and docetaxel chemotherapy. Following rapid approval in Japan and accelerated approval based on phase-II results in the US, a large compassionate-use program has been set up in parallel to extended phase-III testing. Offering therefore access to state-of-the-art therapy to patients who are not candidates for clinical studies; Iressa™ EAP allows physicians to test the new EGFR inhibitor across a heterogeneous patient population characteristic for advanced NSCLC. Patient and methods:: After having treated 240 patients at the Großhansdorf hospital, we have retrospectively analysed the efficacy and tolerability of 250mg/day gefitinib in patients showing a long-term tumor control. We reviewed the patient records of 14 patients with advanced NSCLC that received daily gefitinib for at least 9 months. Results:: Long-term tumor control, defined as confirmed objective tumor response for at least 6 months or disease stabilisation for above 9 months, was observed in chemo-naive patients as well as in fourth-line therapy patients for the latter ones independently of the composition of prior chemotherapy. Most patients (9/14) with such a lasting benefit were female; patients’ histology was in most cases uniform: adenocarcinomas were dominant in women and bronchioloalveolar carcinoma in men. Patients with moderate to severe dyspnoea benefited from a measurable improvement of their respiratory capacity. No cumulative toxicity was observed; characteristic side-effects for gefitinib as grades 1–2 diarrhoea or mild to moderate skin toxicity were well manageable. Conclusion:: For 14 (6%) out of 240 patients with patterns of diffuse disseminated metastatic disease, gefitinib offered a lasting tumor control with a disease progression-free survival interval between 9 and 25 months. In parallel to therapy, patients’ performance status (PS) could be conserved or even improved in many cases. Patients with lung function impairment, as well as patients with other disease-related symptoms obtained additional therapy benefits. [Copyright &y& Elsevier]

Summary: In the treatment of extensive disease of small cell lung cancer (ED SCLC) there is an urgent need for more effective and better-tolerated drug regimens. We report on a prospective phase II trial performed to evaluate the efficacy and safety of a platinum-free regimen—containing topotecan and etoposide—in the first-line treatment of ED SCLC. Between December 1999 and July 2001, 28 chemotherapy-naive patients with ED SCLC were recruited; 9 patients had stage IIIB disease and 19 patients had stage IV disease. Based on phase I results, patients received treatment with intravenous topotecan 1mg/m2 (days 1–5) followed by intravenous etoposide 75mg/m2 (days 8–10). Treatment courses were repeated every 28 days for a maximum of 6 cycles. A confirmed response rate of 46.4% with 1 complete response (CR) and 12 partial responses (PR) (95% CI=27.5–66.1%) was observed. Stable disease (SD) was observed in 18% of patients. The median time to response was 7.9 weeks (range: 7.7–15.1 weeks) and median survival was 29.9 weeks (range from 3.3 to 91.4 weeks). Main toxicities encountered were haematological with Grade III/IV neutropenia in 2.6/1.5% of courses and Grade III/IV thrombocytopenia in 1.8%/0.7% of courses. These toxicities were manageable and were not associated with clinical sequels. Non-haematological toxicities were generally mild with no Grade III/IV toxicities reported apart from Grade III alopecia. The combination therapy of topotecan and etoposide is active in first-line chemotherapy for patients with ED SCLC. The regimen showed a tolerable safety profile. Since drug scheduling plays a critical role in the combination of topoisomerase I and II inhibitors, concurrent administration of topotecan and etoposide might increase the efficacy. [Copyright &y& Elsevier]

Purpose. ZD0473 is a cytotoxic platinum agent, which in preclinical studies has exhibited synergistic activity when combined with paclitaxel. The aim of this open-label phase I study was to determine the maximum tolerated dose (MTD), safety, and antitumour activity of ZD0473 followed by paclitaxel in patients with refractory solid malignancies. Methods. Patients received paclitaxel and ZD0473 on day 1 every 3 weeks. Seven dose levels were planned (ZD0473 60–180 mg/m2, paclitaxel 135–175 mg/m2), with dose escalation dependent on the incidence of dose-limiting toxicity. Results. Included in the study were 23 patients who received 76 treatment cycles at dose levels 1 (60 mg/m2 ZD0473, 135 mg/m2 paclitaxel) to 6 (150 mg/m2 ZD0473, 175 mg/m2 paclitaxel). Dose-limiting thrombocytopenia (platelet count <25×109/l) occurred in two of six patients at dose level 6, which defined the MTD. Grade 3/4 haematological toxicities included: anaemia (21.7%), neutropenia (39.1%), thrombocytopenia (34.8%), and leucopenia (34.8%). The most common grade 3/4 non-haematological toxicities included: alopecia (13.0%), pleural effusion (13.0%), somnolence (8.7%), and vomiting (8.7%). Of the 23 patients, 11 (47.8%) had disease stabilization, including 4 with non-small-cell lung cancer (NSCLC) who had a ≥25% reduction in tumour dimensions. Conclusions. ZD0473 combined with paclitaxel has a manageable tolerability profile and shows some evidence of antitumour activity in patients with NSCLC. [ABSTRACT FROM AUTHOR]

Background: Paclitaxel administered in combination with a topoisomerase-II inhibitor (such as etoposide) and carboplatin is an effective and safe first-line treatment for patients with small-cell lung cancer (SCLC). We conducted a randomized phase III multicenter trial to determine whether paclitaxel plus etoposide plus carboplatin improves the outcome of patients with primary SCLC relative to standard chemotherapy (carboplatin, etoposide, and vincristine).Methods: Between January 1998 and December 1999, 614 patients with SCLC stages I-IV were randomly assigned to the standard arm (309 patients) or the experimental arm (305 patients). Treatment courses were repeated every 21 days for a maximum of six courses. All patients were evaluated for response rate, survival, and toxicities every two courses. The primary endpoint was survival. Survival curves were estimated with the Kaplan-Meier method and compared using the log-rank test. All statistical tests were two-sided.Results: A total of 608 patients were evaluable for all endpoints (standard arm 307 patients, experimental arm 301 patients). The hazard ratio [HR] of death for patients receiving the standard treatment was statistically significantly higher than that for patients receiving the experimental treatment (HR = 1.22, 95% confidence interval [CI] = 1.03 to 1.45; P =.024). Progression-free survival was also statistically significantly shorter for patients in the standard arm relative to that of patients in the experimental arm (HR = 1.21, 95% CI = 1.03 to 1.42). There were no differences in the response rates (complete and partial combined) to the treatments (standard arm: 69.4%, 95% CI = 63.9% to 74.5%; experimental arm: 72.1%, 95% CI = 66.7% to 77.1%; difference = 2.7%, 95% CI = 4.5% to 9.9%). Rates of severe grade of anemia, leukocytopenia, neutropenia, and thrombocytopenia were lower in the experimental arm than in the standard arm.Conclusion: Patients with previously untreated SCLC who received paclitaxel, etoposide, and carboplatin showed improved overall and progression-free survival and less frequent hematologic toxicities than those who received the standard therapy. [ABSTRACT FROM AUTHOR]

Purpose: We evaluated the toxicity and feasibility of adding paclitaxel to a standard platinum/etoposide regimen in the first-line treatment of patients with small cell lung cancer (SCLC). Patients and methods: Eighty-nine patients with limited disease (LD) or extensive disease without distant metastases (ED I) were treated in this multi-centered phase II trial between April 1996 and June 1997. Paclitaxel administration (175 mg/m2 by a 1 h intravenous infusion) was immediately followed by a 30 min infusion of carboplatin at an area under the concentration time curve (AUC) of 5 on day 1 and etoposide 50 mg orally twice daily (bid) was given on days 2–8. Courses were repeated every 21 days. Patients who had an objective response continued treatment for a maximum of 6 courses. Results: Eighty-four patients were assessable for response. Overall response rate (RR) was 82.1% with 17.8% complete remissions and 64.3% partial remissions. Median survival for LD patients was 20.5 months with a 1 year survival rate of 71.4% and a 3 year survival rate of 21.4%. Median survival of ED I patients was 11 months with a 1 year survival rate of 31.3% and a 3 year survival rate of 3.1%. Overall median survival was 18.1 months with a 1 year survival rate of 56.8% and a 3 year survival rate of 14.8%. Median progression-free intervals were 12.3 months for patients with LD stage of the disease and 8 months with ED I stage. Grade 3/4 toxicity was primarily hematologic. Grade 3/4 leucopenia occured in 16.0% of courses and febrile episodes were detected in 0.3% of courses. Non-hematologic toxicities were uncommon. Grade 3 GI-tract toxicities or peripheral neuropathy appeared in less than 1% of the courses. Toxicities were detected according to WHO toxicity criteria. Conclusion: Paclitaxel can be added at full dose (175 mg/m2) to a carboplatin/etoposide combination while maintaining a tolerable toxicity profile. Efficacy data, RR, progression-free interval and survival in both, extensive and limited stage patients compare favorably with other reported data. This new regimen will be further evaluated in comparison to standard regimens in a phase III trial. [Copyright &y& Elsevier]

BACKGROUND Tarlatamab, a bispecific T-cell engager immunotherapy targeting delta-like ligand 3 and CD3, showed promising antitumor activity in a phase 1 trial in patients with previously treated small-cell lung cancer. METHODS In this phase 2 trial, we evaluated the antitumor activity and safety of tarlatamab, administered intravenously every 2 weeks at a dose of 10 mg or 100 mg, in patients with previously treated small-cell lung cancer. The primary end point was objective response (complete or partial response), as assessed by blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS Overall, 220 patients received tarlatamab; patients had previously received a median of two lines of treatment. Among patients evaluated for antitumor activity and survival, the median follow-up was 10.6 months in the 10-mg group and 10.3 months in the 100-mg group. An objective response occurred in 40% (97.5% confidence interval [CI], 29 to 52) of the patients in the 10-mg group and in 32% (97.5% CI, 21 to 44) of those in the 100-mg group. Among patients with an objective response, the duration of response was at least 6 months in 59% (40 of 68 patients). Objective responses at the time of data cutoff were ongoing in 22 of 40 patients (55%) in the 10-mg group and in 16 of 28 patients (57%) in the 100-mg group. The median progression-free survival was 4.9 months (95% CI, 2.9 to 6.7) in the 10-mg group and 3.9 months (95% CI, 2.6 to 4.4) in the 100-mg group; the estimates of overall survival at 9 months were 68% and 66% of patients, respectively. The most common adverse events were cytokine-release syndrome (in 51% of the patients in the 10-mg group and in 61% of those in the 100-mg group), decreased appetite (in 29% and 44%, respectively), and pyrexia (in 35% and 33%). Cytokine-release syndrome occurred primarily during treatment cycle 1, and events in most of the patients were grade 1 or 2 in severity. Grade 3 cytokine-release syndrome occurred less frequently in the 10-mg group (in 1% of the patients) than in the 100-mg group (in 6%). A low percentage of patients (3%) discontinued tarlatamab because of treatment-related adverse events. CONCLUSIONS Tarlatamab, administered as a 10-mg dose every 2 weeks, showed antitumor activity with durable objective responses and promising survival outcomes in patients with previously treated small-cell lung cancer. No new safety signals were identified. (Funded by Amgen; DeLLphi-301 ClinicalTrials.gov number, NCT05060016. opens in new tab.) [ABSTRACT FROM AUTHOR]

In the phase 3 RELAY trial, ramucirumab/erlotinib demonstrated superior progression-free survival (PFS) over placebo/erlotinib in patients with EGFR-mutated metastatic NSCLC (median PFS 19.4 versus 12.4 months; HR = 0.59, 95% CI = 0.46–0.76; p <.0001). Safety was consistent with established profiles for ramucirumab and erlotinib in NSCLC. Here, we present patient-reported outcomes. Patients received oral erlotinib (150 mg daily) plus intravenous ramucirumab (10 mg/kg) or placebo Q2W until progressive disease or unacceptable toxicity. Patients completed the Lung Cancer Symptom Scale (LCSS) and EQ-5D questionnaires at baseline and every other cycle. Analyses included time to deterioration (TtD) for LCSS via Kaplan–Meier method and Cox models and changes from baseline using mixed-model repeated-measures regression analysis. Overall patient compliance for LCSS and EQ-5D was >95%. TtD did not differ between treatment arms for LCSS Total Score (HR = 0.962, 95% CI = 0.690–1.343) and Average Symptom Burden Index (HR = 1.012, 95% CI = 0.732–1.400). TtD of individual LCSS items (appetite loss, fatigue, cough, shortness of breath, pain, symptom distress, difficulties with daily activities, quality of life) indicated no difference between arms; however, patient-reported blood in sputum was worse for ramucirumab/erlotinib (HR = 1.987, 95% CI = 1.206–3.275). Results of LCSS mean changes from baseline were consistent with TtD, indicating no significant differences between treatment arms except for blood in sputum. Mean changes from baseline in EQ-5D index score (p =.94) and visual analogue scale (p =.95) revealed no overall differences in health status between treatment arms. Patients' overall quality of life and symptom burden did not differ with the addition of ramucirumab to erlotinib compared to placebo/erlotinib. These data support the clinical benefit of ramucirumab/erlotinib in untreated EGFR-mutated metastatic NSCLC. [ABSTRACT FROM AUTHOR]

• Immune checkpoint blockade represents a promising treatment in SCLC. • Comprehensive review of anti-PD-(L)1 and anti-CTLA-4 agents in SCLC presented. • Biomarkers under investigation are PD-L1 expression and tumour mutational burden. • Strategies to enhance immune responses and refine patient selection are needed. 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. [ABSTRACT FROM AUTHOR]

Introduction: Studies have shown improved tolerability with once-weekly versus three-weekly docetaxel in the second-line treatment of advanced non-small cell lung cancer (NSCLC). This study aimed to evaluate the tolerability of nintedanib plus weekly docetaxel in patients with NSCLC. Methods: This phase I, open-label, dose-escalation study (NCT02668393) enrolled patients with locally advanced/metastatic adenocarcinoma NSCLC that had progressed on first-line platinum chemotherapy. The primary endpoint was to determine the maximum tolerated dose of nintedanib (up to 200 mg twice daily [BID]) combined with weekly docetaxel (35 mg/m2) on days 1, 8, and 15 based on the occurrence of dose-limiting toxicities (DLTs) over a 28-day treatment cycle. Adverse events (AEs) were also evaluated. Results: The trial terminated prematurely due to recruitment challenges. At termination, seven patients had received nintedanib 150 mg BID and seven nintedanib 200 mg BID, in combination with weekly docetaxel. In the first treatment cycle, DLTs were reported for 1/6 evaluable patients (16.7%) in each group. The disease control rates were 57.1% and 42.9%, respectively. Grade ≥3 treatment-related AEs affected three patients in each group (42.9%); neutropenia was reported in one patient (14.3%) in each group. Treatment-related serious AEs were reported in three patients (42.9%) receiving nintedanib 150 mg, and two patients (28.6%) receiving nintedanib 200 mg. Conclusions: Overall, nintedanib plus weekly docetaxel was well-tolerated in patients with locally advanced or metastatic lung adenocarcinoma who progressed on first-line platinum-based chemotherapy, without loss of efficacy. DLTs were manageable. [ABSTRACT FROM AUTHOR]

Despite immunotherapy advancements for patients with advanced or metastatic non-small-cell lung cancer (NSCLC), pivotal first-line trials were limited to patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1 and a median age of 65 years or younger. We aimed to compare the efficacy and safety of first-line atezolizumab monotherapy with single-agent chemotherapy in patients ineligible for platinum-based chemotherapy. This trial was a phase 3, open-label, randomised controlled study conducted at 91 sites in 23 countries across Asia, Europe, North America, and South America. Eligible patients had stage IIIB or IV NSCLC in whom platinum-doublet chemotherapy was deemed unsuitable by the investigator due to an ECOG PS 2 or 3, or alternatively, being 70 years or older with an ECOG PS 0–1 with substantial comorbidities or contraindications for platinum-doublet chemotherapy. Patients were randomised 2:1 by permuted-block randomisation (block size of six) to receive 1200 mg of atezolizumab given intravenously every 3 weeks or single-agent chemotherapy (vinorelbine [oral or intravenous] or gemcitabine [intravenous]; dosing per local label) at 3-weekly or 4-weekly cycles. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety analyses were conducted in the safety-evaluable population, which included all randomised patients who received any amount of atezolizumab or chemotherapy. This trial is registered with ClinicalTrials.gov , NCT03191786. Between Sept 11, 2017, and Sept 23, 2019, 453 patients were enrolled and randomised to receive atezolizumab (n=302) or chemotherapy (n=151). Atezolizumab improved overall survival compared with chemotherapy (median overall survival 10·3 months [95% CI 9·4–11·9] vs 9·2 months [5·9–11·2]; stratified hazard ratio 0·78 [0·63–0·97], p=0·028), with a 2-year survival rate of 24% (95% CI 19·3–29·4) with atezolizumab compared with 12% (6·7–18·0) with chemotherapy. Compared with chemotherapy, atezolizumab was associated with stabilisation or improvement of patient-reported health-related quality-of-life functioning scales and symptoms and fewer grade 3–4 treatment-related adverse events (49 [16%] of 300 vs 49 [33%] of 147) and treatment-related deaths (three [1%] vs four [3%]). First-line treatment with atezolizumab monotherapy was associated with improved overall survival, a doubling of the 2-year survival rate, maintenance of quality of life, and a favourable safety profile compared with single-agent chemotherapy. These data support atezolizumab monotherapy as a potential first-line treatment option for patients with advanced NSCLC who are ineligible for platinum-based chemotherapy. F Hoffmann-La Roche and Genentech Inc, a member of the Roche group. [ABSTRACT FROM AUTHOR]

A letter to the editor and a response from the authors of the article "Pembrolizumab versus chemotherapy for programmed death 1 ligand (PD-L1)-positive non-small-cell lung cancer" in the November 10, 2016 issue are presented.

Background: Detection of circulating tumour DNA (ctDNA) in biological fluids is a minimally invasive alternative to tissue biopsy for therapy monitoring. Cytokines are released in the tumour microenvironment to influence inflammation and tumorigenic mechanisms. Here, we investigated the potential biomarker utility of circulating cytokines vis-à-vis ctDNA in ALK-rearranged+ lung adenocarcinoma (ALK + NSCLC) and explored the optimal combination of molecular parameters that could indicate disease progression. Methods: Longitudinal serum samples (n = 296) were collected from ALK + NSCLC patients (n = 38) under tyrosine kinase inhibitor (TKI) therapy and assayed to quantify eight cytokines: IFN-γ, IL-1β, IL-6, IL-8, IL-10, IL-12p70, MCP1 and TNF-α. Generalised linear mixed-effect modelling was performed to test the performance of different combinations of cytokines and previously determined ctDNA parameters in identifying progressive disease. Results: Serum IL-6, IL-8 and IL-10 were elevated at progressive disease, with IL-8 having the most significant impact as a biomarker. Integrating changes in IL-8 with ctDNA parameters maximised the performance of the classifiers in identifying disease progression, but this did not significantly outperform the model based on ctDNA alone. Conclusions: Serum cytokine levels are potential disease progression markers in ALK + NSCLC. Further validation in a larger and prospective cohort is necessary to determine whether the addition of cytokine evaluation could improve current tumour monitoring modalities in the clinical setting. [ABSTRACT FROM AUTHOR]

Purpose: Ramucirumab plus docetaxel improved survival in REVEL, a randomized phase 3 trial for patients with Stage IV non-small cell lung cancer after standard platinum-based chemotherapy. This exploratory analysis evaluated the exposure-response relationship of ramucirumab from REVEL.Methods: Patients received ramucirumab (10 mg/kg) or placebo plus docetaxel (75 mg/m2) every 3 weeks. Pharmacokinetic samples were collected. A population pharmacokinetic analysis predicted ramucirumab minimum concentration after first-dose administration (Cmin,1) and average concentration at steady state (Cave,ss). Predicted Cmin,1 and Cave,ss were used to evaluate the relationship between ramucirumab exposure and efficacy and safety, respectively. Exposure-efficacy was assessed by Kaplan-Meier and Cox regression analyses; exposure-safety was assessed by ordered categorical analyses.Results: Analyses included 376 patients treated with ramucirumab plus docetaxel and 366 patients treated with placebo plus docetaxel (364 for safety population). After adjusting for corresponding prognostic factors, the association between overall survival (OS) and Cmin,1 was statistically significant (p = 0.0110), although progression-free survival (PFS) showed a marginal association (p = 0.0515). At high ramucirumab exposures (Cmin,1), greater improvements (smaller hazard ratios) were seen for OS and PFS when stratified by Cmin,1 exposure quartiles. A statistically significant correlation was observed between ramucirumab Cave,ss and grade ≥ 3 febrile neutropenia and hypertension.Conclusions: An association was observed between ramucirumab exposure and efficacy. Higher ramucirumab exposure was associated with improved clinical outcomes and increased toxicity in this analysis. Two exposure-response prospective randomized trials are being conducted to address causation (NCT02443883 and NCT02514551), with encouraging preliminary results (Ajani et al. in Ann Oncol 28:abstr 698P, 2017). [ABSTRACT FROM AUTHOR]

Introduction: Trials of CT‐based screening for lung cancer have shown a mortality advantage for screening in North America and Europe. Before introducing a nationwide lung cancer screening program in Germany, it is important to assess the criteria used in international trials in the German population. Methods: We used data from 3623 lung cancer patients from the data warehouse of the German Center for Lung Research (DZL). We compared the sensitivity of the following lung cancer screening criteria overall and stratified by age and histology: the National Lung Screening Trial (NLST), the Danish Lung Cancer Screening Trial (DLCST), the 2013 and 2021 US Preventive Services Task Force (USPSTF), and an adapted version of the Prostate, Lung, Colorectal, and Ovarian no race model (adapted PLCOm2012) with 6‐year risk thresholds of 1.0%/6 year and 1.7%/6 year. Results: Overall, the adapted PLCOm2012 model (1%/6 years), selected the highest proportion of lung cancer patients for screening (72.4%), followed by the 2021 USPSTF (70.0%), the adapted PLCOm2012 (1.7%/6 year) (57.4%), the 2013 USPTF (57.0%), DLCST criteria (48.7%), and the NLST (48.5%). The adapted PLCOm2012 risk model (1.0%/6 year) had the highest sensitivity for all histological types except for small‐cell and large‐cell carcinomas (non‐significant), whereas the 2021 USPTF selected a higher proportion of patients. The sensitivity levels were higher in males than in females. Conclusion: Using a risk‐based selection score resulted in higher sensitivities compared to criteria using dichotomized age and smoking history. However, gender disparities were apparent in all studied eligibility criteria. In light of increasing lung cancer incidences in women, all selection criteria should be reviewed for ways to close this gender gap, especially when implementing a large‐scale lung cancer screening program. [ABSTRACT FROM AUTHOR]

• Atezolizumab, Bevacizumab, Carboplatin and (nab-)Paclitaxel demonstrates high efficacy and moderate toxicity in uncommon EGFR mutations. • Outcome is independent of type of mutation, smoking status, PD-L1 expression and prior TKI treatment. • Amivantamab remains a treatment option for Exon 20 insertions after ABCP. 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. 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. 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. 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. [ABSTRACT FROM AUTHOR]