Lung Cancer: Targets and Therapy最新文献

Non-small-cell lung cancer (NSCLC) represents about 85% of all lung cancers, and more than half of NSCLCs are diagnosed at an advanced stage. Chemotherapy has reached a plateau in the overall survival curve of about 10 months. Therefore, in last decade novel targeted approaches have been developed to extend survival of these patients, including antiangiogenic treatment. Vascular endothelial growth factor (VEGF) signaling pathway plays a dominant role in stimulating angiogenesis, which is the main process promoting tumor growth and metastasis. Bevacizumab (bev; Avastin^®) is a recombinant humanized monoclonal antibody that neutralizes VEGF's biologic activity through a steric blocking of its binding with VEGF receptor. Currently, bev is the only antiangiogenic agent approved for the first-line treatment of advanced or recurrent nonsquamous NSCLC in "bev-eligible" patients. The ineligibility to receive bev is related to its toxicity. In the pivotal trials of bev in NSCLC, fatal bleeding events including pulmonary hemorrhage were observed with rates higher in the chemotherapy-plus-bev group. Therefore, in order to reduce the incidence of severe pulmonary hemorrhage, numerous exclusion criteria have been characteristically applied for bev such as central tumor localization or tumor cavitation, use of anticoagulant therapy, presence of brain metastases, age of patients (elderly). Subsequent studies designed to evaluate the safety of bev have demonstrated that this agent is safe and well tolerated even in those patients subpopulations excluded from pivotal trials. This review outlines the current state-of-the-art on bev use in advanced NSCLC. It also describes patient selection and future perspectives on this antiangiogenic agent.

Background: Various biomarkers have been shown to predict prognosis in various types of cancers. However, these biomarkers have not been studied in advanced small cell lung cancer (SCLC). The modified Glasgow prognostic score (mGPS) is based on serum albumin level and C-reactive protein (CRP). The prognostic nutritional index (PNI) is a combination of serum albumin level and absolute lymphocyte count. This study aimed to evaluate the prognostic value of mGPS and PNI in SCLC.

Methods: We retrospectively reviewed and calculated mGPS and PNI for patients with stage IIIB or IV SCLC who initiated platinum-based combination chemotherapy between November 2007 and June 2016. We compared overall survival (OS) and progression-free survival (PFS) between high and low groups of these two biomarkers. Univariate and multivariate Cox hazard analyses assessed the prognostic value of these biomarkers.

Results: We reviewed 97 SCLC patients. The OS of patients with mGPS 0-1 and higher PNI was significantly longer than that of those with mGPS 2 and lower PNI. The PFS of mGPS 0-1 was significantly longer than that of mGPS 2, while there was no significant difference in PFS according to PNI. Multivariate analyses found mGPS 0-1 (hazard ratio [HR] 2.34, 95% confidence interval [CI] 1.27-4.31, P<0.01) and higher PNI (HR 0.50, 95% CI 0.31-0.78, P<0.01) as prognostic factors for longer OS. However, neither biomarker was predictive of PFS.

Conclusion: Our study was a small retrospective study; however, the data demonstrate that pretreatment mGPS and PNI are independent predictors of OS in patients with advanced SCLC. The pretreatment assessment of mGPS and PNI may be useful for identification of patients with poor prognosis. We recommend pretreatment measurement of serum albumin, C-reactive protein, and absolute lymphocyte count.

Acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) is a universal event and limits clinical efficacy. The third-generation EGFR inhibitor osimertinib is active in EGFR-mutant/T790M positive non-small-cell lung cancer. Mechanisms of acquired resistance are emerging, and here we describe a cis-oriented solvent-front EGFR G796S mutation as the resistance mechanism observed in a progression biopsy and circulating tumor DNA (ctDNA) from a patient with initial response followed by progression on osimertinib. This is one of the earliest reports of a sole solvent-front tertiary EGFR mutation as a resistance mechanism to osimertinib. Our case suggests a monoclonal resistance mechanism. We review the importance of the solvent-front residues across TKIs and describe known osimertinib resistance mechanisms. We observe that nearly all clinical osimertinib-resistant tertiary EGFR mutations are oriented in cis with EGFR T790M. This case highlights the importance of mutations affecting EGFR kinase domains and supports the feasibility of broad panel ctDNA assays for detection of novel acquired resistance and tumor heterogeneity in routine clinical care.

Lung cancer belongs to malignant tumors that possess the highest rates of morbidity and mortality in the world. A number of morphological, biological and clinical features justify the distinction of small-cell carcinoma with respect to the other histological types of lung cancer. The predominant neuroendocrine phenotype is critical for the selection of biomarkers used in diagnostics, monitoring and evaluation of treatment response; early onset relapses in patients with small-cell lung cancer (SCLC) and the evaluation of their prognosis. Although for a long time the neuron-specific enolase (NSE) was considered to be the marker of choice for this tumor, it is now increasingly important to pay attention to concentrations of pro-gastrin-releasing peptide (ProGRP). The results of this marker have been implicated in the differential diagnosis of non-small lung cancer and SCLC, chemotherapy and radiotherapy monitoring as well as evaluation of treatment response. The subject of this series of studies is to determine the usefulness of ProGRP in the evaluation of patients' prognosis and its predictive value. The current aim for the optimization of the effectiveness of biochemical diagnostics of SCLC is recommended by complementary ProGRP and NSE studies. The present work is a summary of the latest reports regarding diagnostic utility of these markers in SCLC.

Background: The aim of the study was to investigate in terms of noninferiority the efficacy and safety of a monochemotherapy regimen of pemetrexed plus bevacizumab (BevPem) versus carboplatin/pemetrexed plus bevacizumab (BevCPem) in elderly patients as first-line treatment for advanced metastatic or recurrent nonsquamous non-small-cell lung cancer (NSCLC).

Materials and methods: 65Plus was a Phase III, randomized, open-label study. In total, 253 patients received BevPem (n=119) or BevCPem (n=134). The primary outcome measure was progression-free survival. Secondary end points were overall survival, tumor response, and safety outcomes. Evaluations were performed for the whole study population and stratified according to Eastern Cooperative Oncology Group (ECOG) performance status (PS).

Results: Noninferiority of BevPem in comparison to BevCPem could not be demonstrated for the overall population (P=0.7864). Significant superiority of the combined treatment BevCPem was seen in patients of ECOG PS 0-1 (median PFS 5.1 vs 6.9 months, HR 1.353, 95% CI 1.03-1.777), while the opposite tendency was observed in patients with ECOG PS 2 (median PFS 2.9 vs 1.5 months, HR 0.628, 95% CI 0.195-2.025). Overall, better tolerability was found for the BevPem group, irrespective of ECOG PS.

Conclusion: Results from the 65plus study give evidence that BevPem and BevCPem treatments may exert differential effects on PFS, depending on the patients ECOG PS. It appears that patients with better ECOG PS (0-1) benefited more from the combined treatment with carboplatin, while the group comprising more severely impaired patients (ECOG PS 2) benefited more from the monochemotherapy.

Background: Longitudinal data on the impact of treatment on quality of life (QoL) in advanced non-small cell lung cancer (NSCLC) are limited. In this palliative setting, treatment that does not deteriorate QoL is key. Here we report longitudinal QoL in patients with squamous NSCLC, receiving ≤4 cycles of nab-paclitaxel/carboplatin combination chemotherapy.

Methods: Patients received nab-paclitaxel 100 mg/m² days 1, 8, 15 + carboplatin area under the curve 6 mg•min/mL day 1 (q3w) for four cycles. QoL was assessed by the Lung Cancer Symptom Scale (LCSS) and Euro-QoL-5 Dimensions-5 Levels (EQ-5D-5L) at baseline and each cycle (day 1).

Results: Two-hundred and six lesion-response-evaluable patients completed baseline + ≥1 postbaseline QoL assessment and were QoL evaluable. LCSS average total score and symptom burden index improved from baseline throughout four cycles. In the LCSS pulmonary symptoms score, 46% of patients reported clinically meaningful improvement (≥10 mm visual analog scale) from baseline. Individual EQ-5D-5L dimensions remained stable/improved in ≥83% of patients; ≈33% reported complete resolution of baseline problems at least once during four cycles. Generally, responders (unconfirmed complete/partial response) had higher scores vs nonresponders.

Conclusion: In patients with squamous NSCLC, four cycles of nab-paclitaxel/carboplatin demonstrated clinically meaningful QoL improvements, with greater benefits in responders vs nonresponders.

Background: Recommended therapies for advanced/metastatic non-small cell lung cancer (NSCLC) have changed with the advent of targeted therapies. The objectives of this retrospective chart review study were to describe treatment patterns, biomarker testing practices, and health care resource use for advanced NSCLC at 5 sites in Japan.

Patients and methods: We studied anonymized medical record data of patients aged ≥18 years who initiated systemic therapy for newly diagnosed stage IIIB or IV NSCLC from January 2011 through June 2013. Data were analyzed descriptively by histology and mutation status. Overall survival was estimated using the Kaplan-Meier method.

Results: We studied 175 patients, including 43 (25%), 129 (74%), and 3 (2%) with squamous, nonsquamous, and unknown NSCLC histology, respectively; 83% had stage IV NSCLC. Overall, 123 patients (70%) were male; the median age was 70 years (range, 47-86); and 33 (19%) were never-smokers. In the nonsquamous cohort, 105 (81%) and 25 (19%) of patients were tested for epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement, respectively; 44 (42%) had EGFR-positive NSCLC and 2 (8%) had ALK-positive NSCLC, including 26/46 (57%) women and 21/46 (46%) never-smokers. In the squamous cohort, 17 (40%) and 4 (9%), respectively, were tested; 1 EGFR-positive tumor was detected. After first-line therapy, 105 (60%) patients received second-line, and 54/105 (51%; or 31% overall) received third-line therapy. EGFR tyrosine kinase inhibitors were most commonly prescribed for EGFR-positive NSCLC across all lines. In the nonsquamous EGFR/ALK-negative/unknown cohort, most received first-line platinum combinations, particularly younger patients (78% ≥75 years vs 93% <75 years old). The average hospitalization was 21 days/admission. The median (95% CI) overall survival from start of first-line therapy was 9.9 months (7.6-11.7) for all patients and 17.9 months (9.9-24.4) for patients with EGFR/ALK-positive status.

Conclusion: Biomarker testing is common for nonsquamous NSCLC at the 5 Japanese study sites. Treatment is personalized by mutation status and age, per guideline recommendations.

Introduction: Real-world comparative effectiveness, safety, and supportive care use of nab-paclitaxel plus carboplatin vs gemcitabine plus platinum were analyzed in patients with advanced or metastatic squamous cell non-small cell lung cancer (NSCLC).

Materials and methods: Patients who received ≥ 1 cycle of first-line nab-paclitaxel plus carboplatin or gemcitabine plus platinum were identified from the Navigating Cancer database. Clinical effectiveness endpoints included overall survival (OS) and time to treatment discontinuation (TTD). Other endpoints included safety and utilization of supportive care. Cox proportional hazards models were used to control for potential confounding effects of baseline characteristics.

Results: In total, 193 patients were included (nab-paclitaxel plus carboplatin, n = 61; gemcitabine plus platinum, n = 132). Baseline characteristics were generally similar between the cohorts. Patients receiving nab-paclitaxel plus carboplatin had a significantly longer OS than those receiving gemcitabine plus carboplatin (median, 12.8 vs 9.0 months; P = 0.03). However, the adjusted difference was not statistically significant (adjusted HR 1.55; 95% CI, 0.99-2.42; P = 0.06). nab-Paclitaxel plus carboplatin-treated patients had significantly longer TTD than gemcitabine plus carboplatin-treated patients (median, 4.3 vs 3.5 months; P = 0.03; adjusted HR 1.39; 95% CI, 1.01-1.90; P = 0.04). Grade 3 or 4 anemia and neutropenia were significantly lower in patients treated with nab-paclitaxel plus carboplatin vs gemcitabine plus carboplatin. Nausea and neuropathy (grade not specified) were significantly higher in the nab-paclitaxel plus carboplatin than the gemcitabine plus carboplatin group. No differences in supportive care use were observed between the cohorts.

Conclusion: These real-world data support the effectiveness and safety of nab-paclitaxel plus carboplatin for first-line treatment of advanced squamous cell NSCLC.

In the last decade, there have been major therapeutic advances in the management of patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer. Crizotinib was the first approved ALK inhibitor with significant benefits over chemotherapy. However, patients inevitably develop disease progression especially in central nervous system and acquire resistance to crizotinib. Several next-generation ALK inhibitors have been developed to overcome these resistance mechanisms and have demonstrated clinical benefits in crizotinib-refractory non-small cell lung cancer including in central nervous system. Brigatinib is a second-generation ALK inhibitor with high level of activity against ALK and several other targets. It is active in vitro against many ALK kinase domain mutations including L1196M, E1210K, and G1202R which may mediate acquired resistance to other ALK inhibitors. In Phase I/II and ALTA clinical studies, brigatinib has demonstrated substantial and durable responses and intracranial responses after progression on crizotinib. It has acceptable safety profile, but early pulmonary toxicity has been observed prompting to pursue daily dosing of 180 mg (with lead-in). Overall, 180 mg (with lead-in) has showed consistently better efficacy than 90 mg. In this review, we will discuss in detail these two pivotal trials that led to the accelerated approval for brigatinib and its future directions.

Soluble major histocompatibility complex class I polypeptide-related sequence A (sMICA) is a useful marker in surveillance of lung cancer. High serum sMICA level in patients with non-small-cell lung cancer (NSCLC) seems to be a poor prognostic factor being correlated with poor differentiation and advanced stage. However, the low specificity limits its role as a single prognostic marker of NSCLC, but its evaluation, in addition to standard serum markers, could improve the staging of NSCLC. Despite promising, all current studies are insufficient to assess the real efficiency of sMICA as a prognostic marker of NSCLC, and hence, future studies are required to validate it.