Comparison of gefitinib and erlotinib efficacies as third-line therapy for advanced non-small-cell lung cancer

PurposeThe epidermal growth factor receptor inhibitors, gefitinib and erlotinib, are used as standard salvage therapy for advanced non-small-cell lung cancer (NSCLC). The aim of the present study was to compare their efficacies in this population.Patients and methodsThe Taiwan Cancer Registry and the National Health Insurance claim databases were searched for newly diagnosed patients with NSCLC from 2004 to 2007 who received gefitinib or erlotinib as third-line therapy. Overall survival (OS) and time to treatment failure (TTF) were determined from registered parameters. Treatment efficacies were compared by the log-rank test in total population and subsets with different clinical characteristics. The Cox’s proportion hazard model was used to estimate the adjusted hazard ratios in multivariate analyses.ResultsA total of 984 patients who received gefitinib (67%) or erlotinib (33%) were included. Patients receiving gefitinib or erlotinib had similar OS (median, 10.2 versus 9.9 months, p = 0.524) and TTF (median, 5.5 versus 3.4 months, p = 0.103). In multivariate analyses, both treatment groups had similar risk of overall mortality (adjusted hazard ratio [HR] = 1.04, p = 0.629) and treatment failure (adjusted HR = 0.94, p = 0.417). Comparing the treatments in subgroups based on age, tumour histology and gender also revealed no differences in OS and TTF. For patients who received gefitinib or erlotinib for more than 3 or 6 months, there was no difference in TTF but patients who received erlotinib had longer OS.ConclusionsGefitinib and erlotinib had similar efficacies as salvage therapy for advanced NSCLC in Taiwan.     

The frequency and impact of FGFR1 amplification on clinical outcomes in Korean patients with small cell lung cancer

ObjectivesFibroblast growth factor receptor 1 (FGFR1) plays a critical role in many human cancers. We tried to identify the frequency of FGFR1 amplifications among Korean patients with small cell lung cancer (SCLC). Additionally, we examined the clinical significance of FGFR1 amplifications for overall survival (OS) and progression-free survival (PFS) among SCLC patients who received standard chemotherapies.Materials and methodsTumor tissues from 158 Korean patients diagnosed with SCLC from September 2009 to February 2013 were collected and analyzed using an FGFR1 FISH assay with a probe that hybridized to chromosome region 8p12–8p11.23 (Abbott Molecular, Abbott Park, IL).Results and conclusionFGFR1 amplification was detected in three patients (1.9%) harboring extensive disease (ED). A multivariate analysis showed that among the patients with ED, FGFR1 amplification was associated with shorter disease-free survival to first-line chemotherapy with etoposide plus cisplatin or carboplatin (hazard ratio [HR] = 7.1; 95% confidence interval [CI] = 2.0–25.4; P = 0.003). The median overall survival time of the patients with ED was 8.2 and 10.2 months among patients with and without FGFR1 amplification, respectively (P = 0.37). Although FGFR1 amplification is rare in SCLC compared to non-small cell lung cancer or other malignancies with squamous histology, it is associated with poor survival following standard chemotherapy in SCLC. Further studies in large cohorts of patients with SCLC are needed to verify these results. Our results imply that FGFR1 may be a potential therapeutic target in SCLC and it could be confirmed in a clinical trial.     

Outcome of patients with lung adenocarcinoma with transformation to small-cell lung cancer following tyrosine kinase inhibitors treatment: A systematic review and pooled analysis

BackgroundLung adenocarcinoma can transform to small-cell lung cancer (SCLC) when resistance to tyrosine kinase inhibitors (TKIs) develops. This phenomenon has repeatedly been described in several case reports and small patient series. The characteristics and treatment outcomes of this population, however, have not been comprehensively reported.MethodsWe performed a systematic review of the published literature to obtain explorative information on the clinical and pathological features and prognosis of the reported cases.ResultsTwenty-five eligible publications were identified, contributing to 39 patients. The median time from initial diagnosis of lung adenocarcinoma to the transformation to SCLC (ttSCLC) was 19 months (range 1–61 months). The median survival after SCLC diagnosis was 6 months. Female gender was significantly associated with longer ttSCLC at the multivariable analysis. Smoking status seemed to be associated with worse prognosis after the diagnosis of SCLC.ConclusionIn this series of published cases, the transformation to a SCLC phenotype after an initial diagnosis of lung adenocarcinoma following TKI therapy appeared to be a late phenomenon. The prognosis after SCLC diagnosis is poor and current treatment strategies derived from primary SCLC seem to be largely inefficacious. New therapies are needed in the management of transformed SCLC.     

The impact of phosphorylated AMP-activated protein kinase expression on lung cancer survival

BackgroundThe aim of this study is to investigate the prognostic role of phosphorylated AMP-activated protein kinase (pAMPK) in surgically resected non-small-cell lung cancer (NSCLC).MethodsImmunohistochemical staining of pAMPK was carried out on tissue microarrays containing 463 samples obtained from patients with NSCLC and correlated with clinicopathological characteristics and survival.ResultspAMPK expression levels were significantly higher in never smokers versus former smokers versus current smokers (P = 0.045). A positive pAMPK expression was associated with increased overall survival (OS) and recurrence-free survival (RFS) (P = 0.0009 and P = 0.0007, respectively). OS and RFS were statistically superior in pAMPK-positive than in pAMPK-negative patients with adenocarcinoma (ADC; median OS: 5.6 and 4.2 years, respectively, P = 0.0001; median RFS: 5.0 and 2.4 years, respectively, P = 0.001), whereas they were similar in those patients with squamous cell carcinoma. Multivariate analysis confirmed that pAMPK positivity was associated with OS [hazard ratio (HR) = 0.574, 95% confidence interval (CI) 0.418–0.789, P = 0.0006) and RFS (HR = 0.608, 95% CI 0.459–0.807, and P = 0.0006), independent of clinical covariates.ConclusionsHigh pAMPK expression levels are associated with increased survival in patients with NSCLC, especially those with ADC. Our results support further evaluation of AMP-activated protein kinase as a potential prognostic and therapeutic target for lung cancer.     

Clinical assessment of patients with advanced non-small-cell lung cancer eligible for second-line chemotherapy: A prognostic score from individual data of nine randomised trials

PurposeKnowledge of prognostic factors for advanced non-small-cell lung cancer (NSCLC) patients eligible for second-line treatment is scarce. The aim of this study was to assess the prognostic role of a number of routinely collected clinical variables and to provide a summary index to discriminate patients according to probability of survival.MethodsIndividual data from nine randomised trials of second-line treatment in advanced NSCLC were analysed. Primary end-point was overall survival (OS). Cox model, stratified by trial, was used for multivariate analyses, and a prognostic index was provided and validated according to an internal/external procedure.ResultsOut of 1239 patients, 1197 patients (97%) had complete information. Median OS was 7.4 months. At multivariate analysis, prognosis was significantly influenced by gender (worse in males), performance status (PS), tumour histology (worse in squamous and other histology versus adenocarcinoma), stage (worse in IV versus IIIB), type of previous treatment (worse for patients pretreated with platinum) and response to first-line (worse for patients not obtaining objective response). Prognostic score values range from 0 to 14. When three categories were derived, median overall survival values were equal to 11.6, 7.5 and 3.0 months for best (<5), intermediate (5-9) and worst (>9) categories, respectively.ConclusionPrognosis of patients eligible for second-line treatment of advanced NSCLC is significantly conditioned by gender, PS, histology, stage, previous use of platinum and response to first-line. A prognostic score was derived that discriminates well subjects with a relatively more favourable prognosis and those with very short life expectancy.     

Impact of TP53 mutation status on systemic treatment outcome in ALK-rearranged non-small-cell lung cancer

BackgroundWe analyzed whether co-occurring mutations influence the outcome of systemic therapy in ALK-rearranged non-small-cell lung cancer (NSCLC).Patients and methodsALK-rearranged stage IIIB/IV NSCLC patients were analyzed with next-generation sequencing and fluorescence in situ hybridization analyses on a centralized diagnostic platform. Median progression-free survival (PFS) and overall survival (OS) were determined in the total cohort and in treatment-related sub-cohorts. Cox regression analyses were carried out to exclude confounders.ResultsAmong 216 patients with ALK-rearranged NSCLC, the frequency of pathogenic TP53 mutations was 23.8%, while other co-occurring mutations were rare events. In ALK/TP53 co-mutated patients, median PFS and OS were significantly lower compared with TP53 wildtype patients [PFS 3.9 months (95% CI: 2.4–5.6) versus 10.3 months (95% CI: 8.6–12.0), P < 0.001; OS 15.0 months (95% CI: 5.0–24.9) versus 50.0 months (95% CI: 22.9–77.1), P = 0.002]. This difference was confirmed in all treatment-related subgroups including chemotherapy only [PFS first-line chemotherapy 2.6 months (95% CI: 1.3–4.1) versus 6.2 months (95% CI: 1.8–10.5), P = 0.021; OS 2.0 months (95% CI: 0.0–4.6) versus 9.0 months (95% CI: 6.1–11.9), P = 0.035], crizotinib plus chemotherapy [PFS crizotinib 5.0 months (95% CI: 2.9–7.2) versus 14.0 months (95% CI: 8.0–20.1), P < 0.001; OS 17.0 months (95% CI: 6.7–27.3) versus not reached, P = 0.049] and crizotinib followed by next-generation ALK-inhibitor [PFS next-generation inhibitor 5.4 months (95% CI: 0.1–10.7) versus 9.9 months (95% CI: 6.4–13.5), P = 0.039; OS 7.0 months versus 50.0 months (95% CI: not reached), P = 0.001).ConclusionsIn ALK-rearranged NSCLC co-occurring TP53 mutations predict an unfavorable outcome of systemic therapy. Our observations encourage future research to understand the underlying molecular mechanisms and to improve treatment outcome of the ALK/TP53 co-mutated subgroup.     

Systematic review and meta-analysis of randomised,phase II/III trials adding bevacizumab to platinum-based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer

BackgroundPrevious studies have demonstrated the efficacy and safety of bevacizumab in the treatment of non-small-cell lung cancer (NSCLC).MethodsSummary data from randomised trials comparing first-line bevacizumab plus platinum-based chemotherapy with chemotherapy alone for inoperable locally advanced, recurrent or metastatic NSCLC were meta-analysed. Pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and pooled odds ratio (OR) for adverse events were calculated. The chi-squared tests evaluated interactions between treatment effects, and prognostic factors and patient characteristics.ResultsData of 2194 patients (1313 bevacizumab; 881 controls) from four phase II and III trials: AVF-0757g, JO19907, ECOG 4599 and AVAiL, were analysed. Compared with chemotherapy alone, bevacizumab significantly prolonged OS (HR 0.90; 95% confidence interval [CI] 0.81, 0.99; P = 0.03), and PFS (0.72; 95% CI 0.66, 0.79; P < 0.001). Bevacizumab showed a significantly greater effect on OS in patients with adenocarcinoma versus other histologies (P = 0.02), and patients with body weight loss ≤5% versus >5% (P = 0.03). Bevacizumab significantly increased the risk of grade ≥3 proteinuria, hypertension, haemorrhagic events, neutropenia, and febrile neutropenia.ConclusionsBevacizumab significantly prolonged OS and PFS when added to first-line platinum-based chemotherapy in patients with advanced NSCLC; no unexpected toxicity was evident.     

Randomized phase III study of docetaxel plus bavituximab in previously treated advanced non-squamous non-small-cell lung cancer

BackgroundBavituximab is a monoclonal antibody that targets phosphatidylserine in the presence of β₂ glycoprotein 1 (β2GP1) to exert an antitumor immune response. This phase III trial determined the efficacy of bavituximab combined with docetaxel in patients with previously treated advanced non-small-cell lung cancer (NSCLC).Patients and methodsKey eligibility criteria included advanced non-squamous NSCLC with disease progression after treatment with platinum-based doublet chemotherapy, evidence of disease control after at least two cycles of first-line therapy, presence of measurable disease, ECOG performance status 0 or 1, adequate bone marrow and organ function, and no recent history of clinically significant bleeding. Eligible patients were randomized 1 : 1 to receive up to six 21-day cycles of docetaxel plus either weekly bavituximab 3 mg/kg or placebo until progression or toxicity. The primary end point was overall survival (OS).ResultsA total of 597 patients were enrolled. Median OS was 10.5 months in the docetaxel + bavituximab arm and was 10.9 months in the docetaxel + placebo arm (HR 1.06; 95% CI 0.88–1.29; P = 0.533). There was no difference in progression-free survival (HR 1.00; 95% CI 0.82–1.22; P = 0.990). Toxicities were manageable and similar between arms. In subset analysis, among patients with high baseline serum β2GP1 levels ≥200 µg/ml, a nonsignificant OS trend favored the bavituximab arm (HR 0.82; 95% CI 0.63–1.06; P = 0.134). Among patients who received post-study immune checkpoint inhibitor therapy, OS favored the bavituximab arm (HR 0.46; 95% CI 0.26–0.81; P = 0.006).ConclusionsThe combination of bavituximab plus docetaxel is not superior to docetaxel in patients with previously treated advanced NSCLC. The addition of bavituximab to docetaxel does not meaningfully increase toxicity. The potential benefit of bavituximab observed in patients with high β2GP1 levels and in patients subsequently treated with immune checkpoint inhibitors requires further investigation.Clinical trial numberNCT01999673.     

Randomised,placebo-controlled,double-blind,parallel-group phase III study evaluating aflibercept in patients receiving first-line treatment with gemcitabine for metastatic pancreatic cancer

BackgroundThis phase III study investigated the addition of aflibercept to gemcitabine, in patients with advanced pancreatic cancer.Patients and methodsPatients with metastatic pancreatic cancer were randomly assigned to receive either intravenous (i.v.) aflibercept, 4 mg/kg every 2 weeks, or matching placebo combined with gemcitabine, 1000 mg/m² i.v. weekly for 7 weeks out of 8, then weekly for 3 weeks out of 4 until progressive disease, unacceptable toxicity or withdrawal of consent. The primary objective was to demonstrate an improvement in overall survival (OS) between the treatment arms.ResultsThe study was stopped for futility following a planned interim analysis of OS in 427 randomised patients. With a median follow-up of 7.9 months, based on the 546 patients at study termination, median OS was 7.8 months in the gemcitabine plus placebo arm (n = 275) versus 6.5 months in the gemcitabine plus aflibercept arm (n = 271), which was not significant (hazard ratio 1.165, 95% confidence interval (CI) 0.921–1.473, p = 0.2034). Median progression-free survival was 3.7 months in both arms. Treatment discontinuations due to adverse events were more frequent in the aflibercept than in the placebo-containing arm (23% versus 12%).ConclusionAdding aflibercept to gemcitabine did not improve OS in patients with metastatic pancreatic cancer.     

Prophylactic cranial irradiation improved the overall survival of patients with surgically resected small cell lung cancer,but not for stage I disease

ObjectivesWe conducted a retrospective study to evaluate the role of prophylactic cranial irradiation (PCI) on patients with surgically resected small cell lung cancer (SCLC).Patients and methodsBetween January 2003 and December 2009, the records of completely resected patients who were diagnosed with SCLC and definitive pTNM stage on the basis of histological proof were reviewed. According to the therapy modality, patients were allocated to PCI group and non-PCI group.ResultsA total of 193 patients were finally included, 67 patients in PCI group and 126 in non-PCI group. The OS rates at 2-year and 5-year in PCI group were 92.5%, and 54.9%, respectively, and those of non-PCI were 63.2% and 47.8%, respectively (p = 0.005). The BMFS rate at 2-year and 5-year in PCI group was significantly better than those of non-PCI group (96.8%, 76.6% and 79.4%, 75.5%, respectively, p = 0.014). But PCI could not confer survival benefit in the patients with p-stage I. Multivariate analysis revealed that PCI (HR = 2.339; p = 0.001) was an independent prognostic factor of the overall survival.ConclusionsPCI could improve the OS of patients with surgically resected SCLC, but not for p-stage I patients.     

Venous thromboembolism (VTE) in patients with advanced gastric cancer: an Asian experience

BackgroundThe incidence and prognostic impact of venous thromboembolism (VTE) in patients with advanced gastric cancer (AGC) have not been determined. We therefore investigated the incidence of VTE and the clinical characteristics associated with VTE in AGC patients treated with systemic chemotherapy.Patients/MethodsWe retrospectively evaluated the incidence of VTE in 3095 patients diagnosed with inoperable AGC in the Department of Oncology at the Asan Medical Center.ResultsWe found that the 1-year cumulative incidence of VTE was 3.5% and incidence rate was 1.88 events/100 person-years (95% confidence interval, 1.54–2.28 events/100 person-years). Overall survival (OS) was poorer in patients concurrently diagnosed with AGC and VTE than in patients with VTE detected after AGC diagnosis (median OS, 4.5 months versus 10.7 months; HR, 2.171; 95% CI, 1.2–3.93; P = 0.009). Multivariate analysis identified female sex, primary tumour site on the upper portion of stomach (cardia/fundus versus body/antrum), two or more metastatic sites, lung metastasis and increased baseline CA19-9 level as independent risk factors for VTE. OS rates were significantly lower in patients with than without VTE (1-year OS, 40% versus 45.3%; 2-year OS, 10.5% versus 19.3%; HR, 1.23; 95% CI, 1.0–1.52; P = 0.048). Multivariate analysis, however, showed that VTE was not a statistically significant factor affecting survival (P = 0.82).ConclusionsThe incidence rate of VTE was lower in Korean than in Caucasian patients with AGC. VTE was not an independent prognostic factor, although patients with VTE detected at the time of AGC diagnosis had markedly poorer prognosis.     

Cisplatin and gemcitabine in patients with advanced biliary tract cancer (ABC) and persistent jaundice despite optimal stenting: Effective intervention in patients with luminal disease

IntroductionThe advanced biliary tract cancer (ABC)-02 study established cisplatin and gemcitabine (CisGem) as a reference 1^st-line regimen for patients with advanced/metastatic biliary tract cancer; patients with bilirubin ⩾1.5 × upper limit of normal (ULN) were excluded and there are few extant data for systemic treatment in the context of elevated bilirubin.MethodsPatients with ABC, receiving CisGem with a baseline bilirubin of ⩾1.5×ULN were eligible for this retrospective analysis; response, toxicity and survival data were collected.ResultsThirty-three patients of 545 screened; median age 59 years, range 23–79; 58% male, 58% with metastases (79% in the liver) of performance status (PS) 0 (33%), 1 (64%) or 2 (3%) were eligible. The median baseline bilirubin was 55 μmol/L (range 32–286); due to biliary tract obstruction (BTO, 76%) or liver metastases (LM, 24%). Toxicity was comparable to the ABC-02 study; bilirubin normalised in 64% during chemotherapy/follow-up. The median progression-free survival (PFS) was 6.9 months (95% confidence interval (CI): 4.4–9.0) and median overall survival (OS) 9.5 months (95% CI: 5.7–12.8). Patients with BTO had a longer PFS and OS than those with LM (7.0 versus 2.6 months; p = 0.1633 and 9.8 versus 4.4 months, hazard ratio (HR) 0.74; p = 0.465, respectively); not statistically significant (due to small sample size). Normalisation of bilirubin and completion of eight CisGem cycles were associated with longer OS (11.4 versus 2.9 months, HR 0.49; p = 0.08 and 15.2 versus 5.4 months, HR 0.12 p < 0.001, respectively). No difference in OS was shown between the bilirubin percentiles (for either PFS or OS).ConclusionFor PS 0-1 patients with ABC and high bilirubin due to luminal disease despite optimal stenting CisGem can be used safely with results similar to those in patients with normal bilirubin.     

Tolerance and benefits of treatment for elderly patients with limited small-cell lung cancer

ObjectivesOver 20% of all newly diagnosed Dutch patients with small-cell lung cancer (SCLC) are aged ≥ 75 years. Uncertainties still exist about safety and efficacy of chemotherapy and chemoradiation in elderly patients. We evaluated the association between patient characteristics and (completion of) treatment and also evaluated toxicity, response and survival in elderly patients with SCLC.Materials and MethodsPopulation-based data from patients aged 75 years or older and diagnosed with limited SCLC in 1997–2004 in The Netherlands were used (N = 368). Additional data on co-morbidity, motive for deviating from guidelines, grades 3–5 toxicity, response and survival were gathered from medical records.ResultsAlthough only relatively fit elderly were selected for chemotherapy, almost 70% developed toxicity, leading to early termination of chemotherapy in over half of all patients. Median survival time was 6.7 months, but differed strongly according to type and completion of treatment (13.5 months for chemoradiation, 7.1 months for chemotherapy, 2.9 months for best supportive care, 11.5 months for patients receiving at least 4 cycles of chemotherapy and 3.6 months for less than 4 cycles).ConclusionAlthough toxicity rate was high and many patients could not complete the full chemotherapy, those who received chemotherapy or chemoradiation had a significantly better survival. We hypothesize that a better selection by proper geriatric assessments is needed to achieve a more favourable balance between benefit and harm.     

Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin–paclitaxel for chemo-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002)

BackgroundNEJ002 study, comparing gefitinib with carboplatin (CBDCA) and paclitaxel (PTX; Taxol) as the first-line treatment for advanced non-small cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) mutation, previously reported superiority of gefitinib over CBDCA/PTX on progression-free survival (PFS). Subsequent analysis was carried out mainly regarding overall survival (OS).Materials and methodsFor all 228 patients in NEJ002, survival data were updated in December, 2010. Detailed information regarding subsequent chemotherapy after the protocol treatment was also assessed retrospectively and the impact of some key drugs on OS was evaluated.ResultsThe median survival time (MST) was 27.7 months for the gefitinib group, and was 26.6 months for the CBDCA/PTX group (HR, 0.887; P = 0.483). The OS of patients who received platinum throughout their treatment (n = 186) was not statistically different from that of patients who never received platinum (n = 40). The MST of patients treated with gefitinib, platinum, and pemetrexed (PEM) or docetaxel (DOC, Taxotere; n = 76) was around 3 years.ConclusionsNo significant difference in OS was observed between gefitinib and CBDCA/PTX in the NEJ002 study, probably due to a high crossover use of gefitinib in the CBDCA/PTX group. Considering the many benefits and the risk of missing an opportunity to use the most effective agent for EGFR-mutated NSCLC, the first-line gefitinib is strongly recommended.     

A randomised,double-blind,placebo-controlled trial of trametinib,an oral MEK inhibitor,in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas

BackgroundTrametinib, an oral mitogen/extracellular signal-related kinase (MEK)1/2 inhibitor, holds promise for malignancies with rat sarcoma (RAS) mutations, like pancreas cancer. This phase II study was designed to determine overall survival (OS) in patients with pancreas cancer treated with trametinib and gemcitabine. Secondary end-points included progression-free survival (PFS), overall response rate (ORR) and duration of response (DOR); safety end-points were also assessed.MethodsAdults with untreated metastatic adenocarcinoma of the pancreas were randomised (1:1) to receive intravenous gemcitabine 1000 mg/m² (weekly × 7 for 8 weeks, then days 1, 8 and 15 of 28-day cycles) plus trametinib or placebo 2 mg daily. RAS mutations were determined in circulating free DNA (cfDNA) and archival tumour tissue. OS was evaluated in kirsten rat sarcoma viral oncogene homolog (KRAS) mutant and wild-type subgroups.ResultsBaseline characteristics for 160 patients were similar in both treatment arms. There was no significant difference in OS (hazard ratio (HR) 0.98; 95% confidence interval (CI), 0.67–1.44; P = .453); median OS was 8.4 months with gemcitabine plus trametinib and 6.7 months with gemcitabine plus placebo. Median PFS (16 versus 15 weeks), ORR (22% versus 18%) and median DOR (23.9 versus 16.1 weeks) were also similar for trametinib and placebo arms, respectively. KRAS mutation-positive patients (n = 103) showed no difference in OS between arms. Thrombocytopenia, diarrhoea, rash and stomatitis were more frequent with trametinib, as was grade 3 anaemia.ConclusionsThe addition of trametinib to gemcitabine did not improve OS, PFS, ORR or DOR in patients with previously untreated metastatic pancreas cancer. Outcomes were independent of KRAS mutations determined by cfDNA.     

Activity of the Hsp90 inhibitor luminespib among non-small-cell lung cancers harboring EGFR exon 20 insertions

BackgroundThere are currently no approved targeted therapies for non-small-cell lung cancer (NSCLC) patients with EGFR exon 20 insertions (ins20), a subgroup of EGFR mutations that are generally refractory to first/second generation EGFR inhibitors. We report the final results of a phase II trial evaluating the activity of the Hsp90 inhibitor luminespib (AUY922) in NSCLC patients with EGFR ins20.Patients and methodsTwenty-nine patients with stage IV NSCLC with EGFR ins20 identified on local testing and at least one prior therapy were enrolled on the trial between August 2013 and October 2016. The primary end point was objective response rate (ORR), with a pre-determined target rate of effectiveness [defined as the rate of partial response (PR) plus stable disease (SD) lasting ≥3 months] of 20%. Secondary end points were PFS, overall survival (OS), safety and response by EGFR ins20 subtype.ResultsAmong the 29 patients (18 females, median age 60 years) the ORR was 17%, median progression-free survival was 2.9 months (95% CI 1.4–5.6) and median OS (mOS) was 13 months (95% CI 4.9–19.5). The results exceeded the pre-determined target rate of effectiveness with 11/29 (38%) patients having a PR or an SD ≥3 months. The most common luminespib-related toxicities were diarrhea (83%), visual changes (76%) and fatigue (45%). All study treatment was stopped on 28 February 2017 due to dissolution of study drug availability; 3 patients were on treatment at study termination.ConclusionThe study met its primary end point, suggesting that luminespib may be an active therapy for advanced NSCLC patients with EGFR ins20. Luminespib is generally well-tolerated, though reversible low-grade ocular toxicity is common. Further study of luminespib and other hsp90 inhibitors in this population is warranted.Study registration (ClinicalTrials.gov)NCT01854034.     

Sinusal localization of nodal micrometastases is a prognostic factor in breast cancer

BackgroundBreast cancer micrometastases are frequently found during pathological examination of sentinel lymph nodes and complete axillary lymph node dissection. Despite this, their clinical relevance is still debated. The aim of this study is to investigate features that affect disease-free survival (DFS) and overall survival (OS) in patients with nodal micrometastases from breast cancer.Material and methodsWe retrospectively investigated the outcome of 122 patients with nodal micrometastases from breast cancer followed up for 60 months.ResultsAt univariate analysis, worse DFS was related to features of primary tumor (multifocality P = 0.002; size >2 cm, P = 0.022; grade P = 0.022; absence of estrogen P < 0.001 and progesterone P < 0.001 receptors; HER-2 overexpression P = 0.006; vascular invasion P = 0.039; proliferative fraction ≥20% P = 0.034) and micrometastases (sinusal localization P = 0.010). Among the above-mentioned features, two were strongly associated with worse DFS in the multivariate model, i.e. negative receptorial status [hazard ratio (HR) = 11.24, 95% confidence interval (CI) 4.06–31.09; P < 0.001] and sinusal localization of micrometastasis (HR = 3.66, 1.18–11.36; P = 0.025). The OS was influenced by multifocality (P < 0.001) and receptor status (P = 0.005).ConclusionOur results indicate that in patients affected by breast cancer, in addition to the well-known pathological features of primary tumor, sinusal localization of micrometastasis strongly impacts on the prognosis.     

Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry

BackgroundAnti-PD1/PD-L1 directed immune checkpoint inhibitors (ICI) are widely used to treat patients with advanced non-small-cell lung cancer (NSCLC). The activity of ICI across NSCLC harboring oncogenic alterations is poorly characterized. The aim of our study was to address the efficacy of ICI in the context of oncogenic addiction.Patients and methodsWe conducted a retrospective study for patients receiving ICI monotherapy for advanced NSCLC with at least one oncogenic driver alteration. Anonymized data were evaluated for clinicopathologic characteristics and outcomes for ICI therapy: best response (RECIST 1.1), progression-free survival (PFS), and overall survival (OS) from ICI initiation. The primary end point was PFS under ICI. Secondary end points were best response (RECIST 1.1) and OS from ICI initiation.ResultsWe studied 551 patients treated in 24 centers from 10 countries. The molecular alterations involved KRAS (n = 271), EGFR (n = 125), BRAF (n = 43), MET (n = 36), HER2 (n = 29), ALK (n = 23), RET (n = 16), ROS1 (n = 7), and multiple drivers (n = 1). Median age was 60 years, gender ratio was 1 : 1, never/former/current smokers were 28%/51%/21%, respectively, and the majority of tumors were adenocarcinoma. The objective response rate by driver alteration was: KRAS = 26%, BRAF = 24%, ROS1 = 17%, MET = 16%, EGFR = 12%, HER2 = 7%, RET = 6%, and ALK = 0%. In the entire cohort, median PFS was 2.8 months, OS 13.3 months, and the best response rate 19%. In a subgroup analysis, median PFS (in months) was 2.1 for EGFR, 3.2 for KRAS, 2.5 for ALK, 3.1 for BRAF, 2.5 for HER2, 2.1 for RET, and 3.4 for MET. In certain subgroups, PFS was positively associated with PD-L1 expression (KRAS, EGFR) and with smoking status (BRAF, HER2).Conclusions: ICI induced regression in some tumors with actionable driver alterations, but clinical activity was lower compared with the KRAS group and the lack of response in the ALK group was notable. Patients with actionable tumor alterations should receive targeted therapies and chemotherapy before considering immunotherapy as a single agent.     

Referral patterns in advanced non-small cell lung cancer: Impact on delivery of treatment and survival in a contemporary population based cohort

IntroductionChemotherapy improves overall survival (OS) in advanced non-small cell lung cancer (NSCLC), yet low rates of chemotherapy utilization have been observed. We sought to characterize the clinical effectiveness of chemotherapy in the general population by evaluating referral patterns, predictors of chemotherapy receipt and outcomes.MethodsAll referred cases of stage IIIB/IV NSCLC in British Columbia from January 1 to December 31, 2009 were retrospectively reviewed. Patient demographics, tumor characteristics and treatments were extracted. OS was estimated using the Kaplan–Meier method. Cox Proportional Hazards modeling was used to control for confounding variables. Multiple logistic regression was used to assess factors that predicted for chemotherapy treatment.Results1373 patients were identified. Median age 70 years, 53% male, 37% ECOG ≥ 3. Histology: 34% non-squamous, 21% squamous and 46% NOS. 748 (54%) patients were assessed by medical oncology and 417 (30%) received chemotherapy. Predictors of chemotherapy treatment were younger age, ECOG 0–2, living in a rural area and not receiving radiotherapy. There was an improvement in OS in patients who received chemotherapy at 13.1 months versus best supportive care 5.4 months (p < 0.0001). This remained statistically significant when controlling for ECOG, sex, age, histology (HR 0.68, CI 0.59–0.78).ConclusionsIn this population-based setting, 37% of patients had an ECOG ≥ 3 at the time of referral, 54% were assessed by a medical oncologist and only 30% received chemotherapy. This is despite the awareness that chemotherapy significantly improves survival. Strategies to optimize appropriate referral such that patients do not miss out on life-prolonging therapy should be evaluated.