Predictive value of K-ras and PIK3CA in non-small cell lung cancer patients treated with EGFR-TKIs: a systemic review and meta-analysis

Objective

A meta-analysis was performed to augment the insufficient data on the impact of mutative EGFR downstream phosphatidylinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways on the clinical efficiency of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment of non-small cell lung cancer (NSCLC) patients.

Methods

Network databases were explored in April, 2015. Papers that investigated the clinical outcomes of NSCLC patients treated with EGFR-TKIs according to the status of K-ras and/or PIK3CA gene mutation were included. A quantitative meta-analysis was conducted using standard statistical methods. Odds ratios (ORs) for objective response rate (ORR) and hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) were calculated.

Results

Mutation in K-ras significantly predicted poor ORR [OR =0.22; 95% confidence interval (CI), 0.13-0.35], shorter PFS (HR =1.56; 95% CI, 1.27-1.92), and shorter OS (HR =1.59; 95% CI, 1.33-1.91) in NSCLC patients treated with EGFR-TKIs. Mutant PIK3CA significantly predicted shorter OS (HR =1.83; 95% CI, 1.05-3.20), showed poor ORR (OR =0.70; 95% CI, 0.22-2.18), and shorter PFS (HR =1.79; 95% CI, 0.91-3.53) in NSCLC patients treated with EGFR-TKIs.

Conclusion

K-ras mutation adversely affected the clinical response and survival of NSCLC patients treated with EGFR-TKIs. PIK3CA mutation showed similar trends. In addition to EGFR, adding K-ras and PIK3CA as routine gene biomarkers in clinical genetic analysis is valuable to optimize the effectiveness of EGFR-TKI regimens and identify optimal patients who will benefit from EGFR-TKI treatment.KEYWORDS : Non-small cell lung cancer (NSCLC), tyrosine kinase inhibitor (TKI), targeted therapy, K-ras, PIK3CA, meta-analysis     

Induction gemcitabine in standard dose or prolonged low-dose with cisplatin followed by concurrent radiochemotherapy in locally advanced non-small cell lung cancer: a randomized phase II clinical trial

Background

The optimal combination of chemotherapy with radiation therapy for treatment locally advanced non-small cell lung cancer (NSCLC) remains an open issue. This randomized phase II study compared gemcitabine in two different schedules and cisplatin - as induction chemotherapy, followed by radiation therapy concurrent with cisplatin and etoposid.

Patients and methods.

Eligible patients had microscopically confirmed inoperable non-metastatic non-small cell lung cancer; fulfilled the standard criteria for platin-based chemotherapy; and signed informed consent. Patients were treated with 3 cycles of induction chemotherapy with gemcitabine and cisplatin. Two different aplications of gemcitabine were compared: patients in arm A received gemcitabine at 1250 mg/m² in a standard half hour i.v. infusion on days 1 and 8; patients in arm B received gemcitabine at 250 mg/m² in prolonged 6-hours i.v. infusion on days 1 and 8. In both arms, cisplatin 75 mg/m² on day 2 was administered. All patients continued treatment with radiation therapy with 60–66 Gy concurrent with cisplatin 50 mg/m² on days 1, 8, 29 and 36 and etoposid 50 mg/m² on days 1–5 and 29–33. The primary endpoint was response rate (RR) after induction chemotherapy; secondary endpoints were toxicity, progression-free survival (PFS) and overall survival (OS).

Results

From September 2005 to November 2010, 106 patients were recruited to this study. No statistically signifficant differences were found in RR after induction chemotherapy between the two arms (48.1% and 57.4%, p = 0.34). Toxicity profile was comparable and mild with grade 3/4 neutropenia as primary toxicity in both arms. One patient in arm B suffered from acute peripheral ischemia grade 4 and an amputation of lower limb was needed. With a median follow-up of 69.3 months, progression-free survival and median survival in arm A were 15.7 and 24.8 months compared to 18.9 and 28.6 months in arm B. The figures for 1- and 3-year overall survival were 73.1% and 30.8% in arm A, and 81.5 % and 44.4% in arm B, respectively.

Conclusions

Among the two cisplatin-based doublets of induction chemotherapy for inoperable NSCLC, both schedules of gemcitabine have a comparable toxicity profile. Figures for RR, PFS and OS are among the best reported in current literature. While there is a trend towards better efficacy of the treament with prolonged infusion of gemcitabine, the difference between the two arms did not reach statistical significance.     

EGFR gene copy number as a predictive biomarker for resistance to anti-EGFR monoclonal antibodies in metastatic colorectal cancer treatment:a meta-analysis简

Objective：The epidermal growth factor receptor （EGFR） inhibitors monoclonal antibodies （MoAbs） have already shown the therapeutic effectiveness in patients with metastatic colorectal cancer （mCRC）.But many patients resist to the treatment.The aim of this meta-analysis was to assess EGFR gene copy number （GCN） as a candidate predictive biomarker for resistance to anti-EGFR MoAbs in mCRC treatment.Methods：Systematic computerized searches of the PubMed,EMBase and Cochrane Library were performed.The primary endpoint was objective response rate （ORR）.The second endpoints included progression-free survival （PFS）,and overall survival （OS）.The pooled odd ratio （OR） and pooled sensitivity,specificity,and summary receiver operator characteristic （SROC） for ORR were estimated.The pooled hazard ratios （HR） for PFS and OS were also calculated.Results：Fourteen studies with 1,021 patients were included.Increased EGFR GCN was associated with increased ORR （OR=6.905; 95％ CI：4.489-10.620）.It was also found in wild-type KRAS mCRC patients,with the pooled OR of 8.133 （95 ％ CI：4.316-15.326）.GCN has medium value for predicting ORR,with the pooled sensitivity of 0.79 （95％ CI：0.73-0.84）,the pooled specificity of 0.59 （95％ CI：0.55-0.62）.In wildtype KRAS mCRC patients,the sensitivity and the specificity were 0.80 （95％ CI：0.70-0.87） and 0.60 （95％CI：0.53-0.66）,respectively.Increased EGFR GCN was associated with increased PFS （HR=0.557; 95％ CI：0.382-0.732） and OS （HR=0.579; 95％ CI：0.422-0.737）.Conclusions：This meta-analysis suggests that EGFR GCN represents a predictive biomarker for tumor response in mCRC patients treated with MoAbs regardless of KRAS mutation.mCRC patients with increased EGFR GCN are more likely to have a better response,PFS,and OS when treated with cetuximab or panitumumab.     

Epidermal growth factor receptor mutation analysis in cytological specimens and responsiveness to gefitinib in advanced non-small cell lung cancer patients

Background

Epidermal growth factor receptor (EGFR) mutation is the key predictor of EGFR tyrosine kinase inhibitors (TKIs) efficacy in non-small cell lung cancer (NSCLC). We conducted this study to verify the feasibility of EGFR mutation analysis in cytological specimens and investigate the responsiveness to gefitinib treatment in patients carrying EGFR mutations.

Methods

A total of 210 cytological specimens were collected for EGFR mutation detection by both direct sequencing and amplification refractory mutation system (ARMS). We analyzed EGFR mutation status by both methods and evaluated the responsiveness to gefitinib treatment in patients harboring EGFR mutations by overall response rate (ORR), disease control rate (DCR) and progression free survival (PFS).

Results

Of all patients, EGFR mutation rate was 28.6% (60/210) by direct sequencing and 45.2% (95/210) by ARMS (P<0.001) respectively. Among the EGFR wild type patients tested by direct sequencing, 26.7% of them were positive by ARMS. For the 72 EGFR mutation positive patients treated with gefitinib, the ORR, DCR and median PFS were 69.4%, 90.2% and 9.3 months respectively. The patients whose EGFR mutation status was negative by direct sequencing but positive by ARMS had lower ORR (48.0% vs. 80.9%, P=0.004) and shorter median PFS (7.4 vs. 10.5 months, P=0.009) as compared with that of EGFR mutation positive patients by both detection methods.

Conclusions

Our study verified the feasibility of EGFR analysis in cytological specimens in advanced NSCLC. ARMS is more sensitive than direct sequencing in EGFR mutation detection. EGFR Mutation status tested on cytological samples is applicable for predicting the response to gefitinib. Abundance of EGFR mutations might have an influence on TKIs efficacy.     

Phase II study of continuous daily sunitinib dosing in patients with previously treated advanced non-small cell lung cancer

Background:

Sunitinib malate (SUTENT) has promising single-agent activity given on Schedule 4/2 (4 weeks on treatment followed by 2 weeks off treatment) in advanced non-small cell lung cancer (NSCLC).

Methods:

We examined the activity of sunitinib on a continuous daily dosing (CDD) schedule in an open-label, multicentre phase II study in patients with previously treated, advanced NSCLC. Patients ⩾18 years with stage IIIB/IV NSCLC after failure with platinum-based chemotherapy, received sunitinib 37.5 mg per day. The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), overall survival (OS), 1-year survival rate, and safety.

Results:

Of 47 patients receiving sunitinib, one patient achieved a confirmed partial response (ORR 2.1% (95% confidence interval (CI) 0.1, 11.3)) and 11 (23.4%) had stable disease (SD) ⩾8 weeks. Five patients had SD>6 months. Median PFS was 11.9 weeks (95% CI 8.6, 14.1) and median OS was 37.1 weeks (95% CI 31.1, 69.7). The 1-year survival probability was 38.4% (95% CI 24.2, 52.5). Treatment was generally well tolerated.

Conclusions:

The safety profile and time-to-event analyses, albeit relatively low response rate of 2%, suggest single-agent sunitinib on a CDD schedule may be a potential therapeutic agent for patients with advanced, refractory NSCLC.     

FOLFOX4 plus cetuximab administered weekly or every second week in the first-line treatment of patients with KRAS wild-type metastatic colorectal cancer: a randomized phase II CECOG study

BackgroundThis randomized phase II study investigated first-line chemotherapy plus cetuximab administered every second week in KRAS wild-type metastatic colorectal cancer.Patients and methodsPatients received FOLFOX4 plus either standard weekly cetuximab (arm 1) or cetuximab (500 mg/m²) every second week (arm 2), until disease progression or unacceptable toxicity. Primary end point was the objective response rate (ORR). Progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety were also investigated. The study was not powered to establish non-inferiority, but aimed at the estimation of treatment differences.ResultsOf 152 randomized eligible patients, 75 were treated in arm 1 and 77 in arm 2; ORRs [53% versus 62%, odds ratio 1.40, 95% confidence interval (CI) 0.74–2.66], PFS [median 9.5 versus 9.2 months, hazard ratio (HR) 0.92, 95% CI 0.63–1.34], OS (median 25.8 versus 23.0 months, HR 0.86, 95% CI 0.56–1.30) and DCR (87%) were comparable. HRs adjusted for baseline factors were 1.01 and 0.99 for PFS and OS, respectively. Frequencies of grade 3/4 adverse events in arms 1 versus 2 were similar: most common were neutropenia (28% versus 34%) and rash (15% versus 17%).ConclusionsActivity and safety of FOLFOX4 plus either cetuximab administered weekly or every second week were similar.     

Association Between Immune-related Adverse Events and Efficacy of Immune Checkpoint Inhibitors in Non–small-cell Lung Cancer

BackgroundImmune checkpoint inhibitors (ICIs) are available for first- and further lines of treatment of patients with advanced non–small-cell lung cancer (NSCLC). These treatments are associated with adverse events called immune-related adverse events (IRAEs). The incidence, diagnosis, and treatment of IRAEs are quite acknowledged; however, the link between IRAEs and the efficacy of ICIs requires further clarification. The objectives of this study were to assess the association between IRAEs incidence and severity and ICIs efficacy in patients with advanced NSCLC.MethodsIn this retrospective study, clinical, biological, treatment, and outcome data were collected from patients with advanced NSCLC who received at least 1 cycle of ICIs from April 2013 to February 2017. The primary endpoint was to assess the association of IRAEs incidence with overall survival (OS). Secondary endpoints were the association of IRAEs with progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR).ResultsOverall, 270 patients were studied. The median OS was 14 months, median PFS was 2.6 months, ORR was 13%, and DCR was 51%. OS, PFS, and ORR were significantly better for patients with IRAEs compared with patients with no IRAEs, translating to median OS not reached versus 8.21 months, respectively (hazard ratio, 0.29; 95% confidence interval [CI], 0.18-0.46; P < .001); PFS was 5.2 versus 1.97 months (hazard ratio, 0.42; 95% CI, 0.32-0.57; P < .001); and ORR was 212.9% versus 5.7% (odds ratio, 4.9; 95% CI, 2.18-11.05; P < .001).ConclusionsThis report presents the largest case series showing longer OS and PFS and better ORR when IRAEs occurred in a population of patients with advanced NSCLC treated with ICIs. The biological background for this phenomenon is being explored prospectively.     

Upfront,randomized, phase 2 trial of sorafenib versus sorafenib and low‐dose interferon alfa in patients with advanced renal cell carcinoma

BACKGROUND:

The objective of this study was to independently evaluate the objective response rate of sorafenib and sorafenib plus low‐dose interferon‐alfa 2b (IFN) as frontline therapy in patients with metastatic renal cell carcinoma (mRCC).

METHODS:

Untreated patients with clear cell mRCC were randomized to receive sorafenib 400 mg orally twice daily or sorafenib 400 mg orally twice daily plus subcutaneous IFN 0.5 million U (MU) twice daily. Primary endpoints included the objective response rate (ORR) and safety. Secondary endpoints included progression‐free survival (PFS) and overall survival (OS). Exploratory endpoints included the predictive value of tumor tissue biomarkers.

RESULTS:

Eighty patients were enrolled. The median follow‐up was 19.7 months (range, 0‐34.2 months). The ORR was 30% (95% confidence interval [CI], 16.6%‐46.5%) in the sorafenib arm and 25% (95% CI, 12.7%‐41.2%) in the combination arm. The median PFS was 7.39 months in the sorafenib‐alone arm (95% CI, 5.52‐9.20 months) and 7.56 months in the sorafenib plus IFN arm (95% CI, 5.19‐11.07 months). The median OS was 27.04 months in the combination arm (95% CI, from 22.31 to not attained) and was not reached in the sorafenib arm. Toxicities were comparable in both arms. In a multivariate model, increased phosphorylated protein kinase B (pAKT) levels were associated with poorer PFS (hazard ratio, 1.04; 95% CI, 1.00‐1.08; P = .0411) and OS (hazard ratio, 1.15; 95% CI, 1.02‐1.29; P = .0173).

CONCLUSIONS:

The addition of low‐dose IFN to sorafenib resulted in efficacy outcomes that were comparable to those achieved with sorafenib monotherapy. The current results indicated that pAKT levels may predict for clinical outcome, but further mechanistic study is required. Cancer 2010. © 2010 American Cancer Society.     

Nedaplatin/gemcitabine versus carboplatin/gemcitabine in treatment of advanced non-small cell lung cancer: A randomized clinical trial

Objective: To evaluate the efficacy and safety of nedaplatin/gemcitabine (NG) and carboplatin/gemcitabine (CG) in the management of untreated advanced non‐small cell lung cancer (NSCLC). Methods: Sixty‐two patients with previously untreated advanced NSCLC were recruited between June 2006 and November 2007. Subjects were randomly assigned to the NG arm (n=30) and the CG arm (n=32). Only patients (24 and 25 in the NG and CG arms, respectively) who completed ≥2 chemotherapy cycles were included in the data analysis. The primary outcome measure was the objective response rate (ORR). The secondary outcome measures included progression‐free survival (PFS), overall survival (OS) and adverse events. Results: There were no statistically significant differences in the efficacy measures (ORR, P=0.305; median PFS, P=0.198; median OS, P=0.961) or in the major adverse events (grade 3/4 neutropenia, P=0.666; grade 3/4 anemia, P=0.263; grade 3/4 thrombocytopenia, P=0.212) between the two treatment arms. However, there was a trend towards higher ORR (37.5% vs. 24.0%), longer PFS (6.0 vs. 5.0 months), and less adverse events in the NG arm. Conclusion: NG regimen seems to be superior over CG regimen for advance NSCLS, but further investigation is needed to validate this superiority.     

Preoperative chemotherapy prior to pulmonary metastasectomy in surgically resected primary colorectal carcinoma

Background

The benefit of preoperative chemotherapy prior to pulmonary metastasectomy for patients with colorectal carcinoma (CRC) is unknown. Here, we identify outcomes of preoperative chemotherapy in patients with resected primary CRC who then underwent pulmonary metastasectomy.

Methods

We queried a prospective database to identify treatment characteristics. Multivariate analyses identified predictors of overall survival (OS) and progression-free survival (PFS).

Results

229 patients underwent lung metastasectomy, of whom 115 proceeded to surgery without chemotherapy while 114 received preoperative regimen based on oxaliplatin (32%), irinotecan (46%), capecitabine (16%), or other (6%). Median PFS in preoperative chemotherapy vs. surgery alone arms were comparable (p=0.004). Patients on oxaliplatin-based therapy had an improved OS vs. an irinotecan, capecitabine, or alternate regimen (p=.019). On multivariate analysis, the irinotecan subset had a worse OS (HR 1.846; 95% CI 1.070, 3.185) vs. surgery alone arm (p=0.028). The OS of an oxaliplatin-based regimen vs. no chemotherapy was inconclusive (HR 0.57; 95% CI 0.237 to 1.389, p=0.218). Multivariate analysis demonstrated a worse PFS and OS for the male gender and an incomplete resection (R2).

Conclusion

Prospective trials on specific preoperative regimens and criteria for patient selection may identify a role for preoperative chemotherapy prior to a curative pulmonary metastasectomy.     

Progression-free survival as a surrogate endpoint for overall survival in glioblastoma: a literature-based meta-analysis from 91 trials

Background

The aim of this study was to determine correlations between progression-free survival (PFS) and the objective response rate (ORR) with overall survival (OS) in glioblastoma and to evaluate their potential use as surrogates for OS.

Method

Published glioblastoma trials reporting OS and ORR and/or PFS with sufficient detail were included in correlative analyses using weighted linear regression.

Results

Of 274 published unique glioblastoma trials, 91 were included. PFS and OS hazard ratios were strongly correlated; R² = 0.92 (95% confidence interval [CI], 0.71–0.99). Linear regression determined that a 10% PFS risk reduction would yield an 8.1% ± 0.8% OS risk reduction. R² between median PFS and median OS was 0.70 (95% CI, 0.59–0.79), with a higher value in trials using Response Assessment in Neuro-Oncology (RANO; R² = 0.96, n = 8) versus Macdonald criteria (R² = 0.70; n = 83). No significant differences were demonstrated between temozolomide- and bevacizumab-containing regimens (P = .10) or between trials using RANO and Macdonald criteria (P = .49). The regression line slope between median PFS and OS was significantly higher in newly diagnosed versus recurrent disease (0.58 vs 0.35, P = .04). R² for 6-month PFS with 1-year OS and median OS were 0.60 (95% CI, 0.37–0.77) and 0.64 (95% CI, 0.42–0.77), respectively. Objective response rate and OS were poorly correlated (R² = 0.22).

Conclusion

In glioblastoma, PFS and OS are strongly correlated, indicating that PFS may be an appropriate surrogate for OS. Compared with OS, PFS offers earlier assessment and higher statistical power at the time of analysis.     

First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV,open-label,single-arm study

Background:

Phase-IV, open-label, single-arm study ({"type":"clinical-trial","attrs":{"text":"NCT01203917","term_id":"NCT01203917"}}NCT01203917) to assess efficacy and safety/tolerability of first-line gefitinib in Caucasian patients with stage IIIA/B/IV, epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC).

Methods:

Treatment: gefitinib 250 mg day⁻¹ until progression. Primary endpoint: objective response rate (ORR). Secondary endpoints: disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety/tolerability. Pre-planned exploratory objective: EGFR mutation analysis in matched tumour and plasma samples.

Results:

Of 1060 screened patients with NSCLC (859 known mutation status; 118 positive, mutation frequency 14%), 106 with EGFR sensitising mutations were enrolled (female 70.8% adenocarcinoma 97.2% never-smoker 64.2%). At data cutoff: ORR 69.8% (95% confidence interval (CI) 60.5–77.7), DCR 90.6% (95% CI 83.5–94.8), median PFS 9.7 months (95% CI 8.5–11.0), median OS 19.2 months (95% CI 17.0–NC; 27% maturity). Most common adverse events (AEs; any grade): rash (44.9%), diarrhoea (30.8%); CTC (Common Toxicity Criteria) grade 3/4 AEs: 15% SAEs: 19%. Baseline plasma 1 samples were available in 803 patients (784 known mutation status; 82 positive; mutation frequency 10%). Plasma 1 EGFR mutation test sensitivity: 65.7% (95% CI 55.8–74.7).

Conclusion:

First-line gefitinib was effective and well tolerated in Caucasian patients with EGFR mutation-positive NSCLC. Plasma samples could be considered for mutation analysis if tumour tissue is unavailable.     

A Randomized,Multicenter, Phase II Study of Cetuximab With Docetaxel and Cisplatin as Induction Chemotherapy in Unresectable,Locally Advanced Head and Neck Cancer

Lessons Learned

• Addition of cetuximab may affect tolerability and, in turn, affect eventual outcomes.
• The incidence of prior human papillomavirus infection has emerged as an important variable that can confound trials enrolling patients with oropharyngeal cancer.

Background.

We investigated the efficacy of cetuximab when added to induction chemotherapy followed by concurrent chemoradiotherapy (CCRT) in patients with locally advanced head and neck squamous cell carcinoma.

Methods.

Patients were randomized to receive three cycles of docetaxel and cisplatin (TP regimen) with or without cetuximab (TP plus cetuximab [CTP] vs. TP) as induction chemotherapy. Patients in the CTP arm received CCRT with cetuximab and cisplatin, whereas patients in the TP arm received cisplatin alone. The primary endpoint was the objective response rate (ORR) after induction chemotherapy.

Results.

Overall, 92 patients were enrolled. The ORRs for induction chemotherapy in the CTP and TP arms were not different (81% vs. 82%). Adding cetuximab lowered the completion rate of induction chemotherapy and CCRT and resulted in more frequent dose reductions of the induction chemotherapy, although this did not reach statistical significance. In the CTP and TP arms, respectively, the 3-year progression-free survival (PFS) rates were 70% and 56% (p = .359), and the overall survival (OS) rates were 88% and 74% (p = .313). When limited to patients who completed induction chemotherapy, 3-year PFS rates of 78% and 59% (p = .085) and OS rates of 94% and 73% (p = .045) were observed in the CTP and TP arms, respectively.

Conclusion.

Adding cetuximab to sequential treatment did not increase the treatment efficacy and resulted in greater toxicity. In the intent-to-treat population, neither PFS nor OS was improved by the addition of cetuximab to sequential treatment; however, a suggestion of improved survival outcomes was observed in patients completing cetuximab-containing induction chemotherapy.     

Correlation between overall survival and other endpoints in clinical trials of second-line chemotherapy for patients with advanced gastric cancer

Background

The correlation between progression-free survival (PFS) or time to progression (TTP) and overall survival (OS) has been evaluated in patients with advanced gastric cancer (AGC) who received first-line chemotherapy. No corresponding analysis has been done in patients who have undergone second-line chemotherapy.

Methods

We evaluated the correlation between PFS, TTP, objective response rate (ORR), disease control rate (DCR), and OS in patients with AGC who underwent second-line chemotherapy. Correlations were evaluated by Spearman rank correlation coefficient (ρ).

Results

Sixty-four trials, including 10 randomized studies, were selected for analysis. Median PFS/TTP moderately correlated with OS (ρ = 0.56). The correlation tended to be stronger in non-Asian trials (ρ = 0.74) than in Asian trials (ρ = 0.37). ORR and DCR did not strongly correlate with OS (ρ = 0.38 for ORR; ρ = 0.54 for DCR). The hazard ratio of PFS and OS in each of the arms of the 10 randomized studies also showed a low correlation (ρ = 0.36).

Conclusions

PFS/TTP, ORR, and DCR did not correlate sufficiently with OS to be used as surrogate endpoints in patients with AGC who have undergone second-line chemotherapy. Further research is needed based on individual patient data from ongoing randomized trials.     

Predictive factors associated with gefitinib response in patients with advanced non-small-cell lung cancer （NSCLC）

Purpose： A number of different clinical characteristics have been reported to singly correlate with therapeutic activity of epidermal growth factor receptor （EGFR） tyrosine kinase inhibitors （TKIs） in advanced non-small-cell lung cancer （NSCLC）. This study aimed to identify predictive factors associated with prognostic benefits of gefitinib. Patients and methods： EGFR gene typing in 33 advanced NSCLC patients received gefitinib （250 mg/day） were analyzed with mutant-enriched PCR assay. Gefitinib response was evaluated with potential predictive factors retrospectively. Results： The overall objective response rate （ORR） and median progression-flee survival （PFS） in the 33 patients treated by gefitinib were 45.5% and 3.0 （2.0-4.0） months. The ORR and median PFS in EGFR gene mutation patients were significantly higher/longer than those in EGFR gene wild-type patients （P〈0.01）. Similarly, the ORR and median PFS in non-smoker patients were significantly higher/longer than those in smoker patients （P〈0.05, P〈0.01, respectively）. However, no difference for ORR and median PFS occurred between male and female patients. Logistic multivariate analysis showed that only EGFR mutated gene was significantly associated with the ORR （P〈0.01）. Both EGFR mutated gene and non-smoker were the major factors that contributed to PFS （P〈0.05）. Conclusions： EGFR mutated gene and non-smoker status are potential predictors for gefitinib response in NSCLC patients.     

A Pooled Analysis of Gemcitabine Plus Docetaxel Versus Capecitabine Plus Docetaxel in Metastatic Breast Cancer

Introduction.

In two randomized phase III trials of patients with metastatic breast cancer (MBC), gemcitabine-docetaxel (GD) and capecitabine-docetaxel (CD) had similar efficacy, but distinct safety profiles.

Methods.

Data from two GD versus CD studies were pooled; overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) were determined. Cox proportional hazards models identified prognostic factors associated with improved OS and PFS. Using a multivariate prognostic model incorporating identified adverse prognostic factors, we grouped MBC patients into low-, intermediate-, and high-risk categories. Hazard ratios (HRs) of GD over CD for OS and PFS were determined for subsets of patients.

Results.

Baseline demographics of the pooled population were mostly well balanced. In the pooled population, there were no significant differences between GD versus CD for OS (HR = 1.02; p = .824), PFS (HR = 1.15; p = .079), and ORR (p = .526). In the pooled crossover population, there were trends toward improved OS (HR = 0.82; p = .171) and PFS (HR = 0.93; p = .557) with GD. Several prognostic factors (including prior adjuvant taxane) for improved OS or PFS were identified; however, there were no significant interactions between treatment arms and prognostic factors for PFS or OS, except number of metastatic sites. In the prognostic model, median OS and PFS were numerically lower in the high-risk group versus the intermediate- and low-risk groups.

Conclusion.

This analysis confirms the lack of efficacy difference between GD and CD in the pooled population, crossover population, and almost all subpopulations. Several prognostic factors were associated with improved outcomes in the pooled population.     

白蛋白紫杉醇复治Ⅳ期非小细胞肺癌的临床疗效

目的:评价白蛋白紫杉醇(nab-p)复治Ⅳ期非小细胞肺癌(NSCLC)的近期疗效和安全性。方法:回顾分析28例使用nab-p单药化疗的Ⅳ期NSCLC患者,其经过一线或一线以上的抗肿瘤治疗后疾病进展,随后接受nab-p 130mg/m2 d1、d8,21天为1周期方案,观察近期疗效、无进展生存期(PFS)及毒性反应,并对病理类型及年龄进行亚组分析。结果:28例患者中,CR 0例(0%),PR 6例(21.4%),SD 13例(46.4%),PD 9例(32.1%),ORR 21.4%,DCR 67.9%,中位PFS 4.2个月。主要的III级毒性包括中性粒细胞减少(17.9%),周围神经毒性(3.57%)及血小板减少(3.57%),出现1例Ⅳ度骨髓抑制。鳞癌患者的ORR (23.1%vs 20.0%,P=0.843)及中位PFS(4.6 vs 4.2个月,P=0.433)较非鳞癌有提高趋势。老年肺癌患者的ORR为22.2%,DCR为66.7%,中位PFS为4.2个月,疗效优且耐受性佳。结论:nab-p复治Ⅳ期NSCLC显示出较好的疗效,毒副作用可耐受,肺鳞癌可能能更好的从nab-p中获益,对老年患者高效低毒,值得进一步进行大样本研究。     

A phase II study of pemetrexed in patients with previously heavily treated non-squamous non-small cell lung cancer (HANSHIN Oncology Group 001)

Purpose

Pemetrexed has shown substantial activity in non-squamous non-small cell lung cancer (NSCLC) and is one of the current standard agents in second-line settings due to its efficacy and favorable tolerability profile. We conducted phase II study to evaluate the safety and efficacy of pemetrexed in Japanese patients with previously heavily treated, advanced non-squamous NSCLC.

Methods

Patients with stage IIIB or IV non-squamous NSCLC, performance status (PS) 0–2, previous two to five regimens of chemotherapy were enrolled and received pemetrexed (500 mg/m²) on day 1 every 21 days until disease progression. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety.

Results

From August 2009 to May 2010, 46 patients were enrolled: median age 65 years; 52 % women; PS 0/1/2 26/67/7 %; previous treatment regimen 2/3/4/5 48/28/20/4 %; epidermal growth factor receptor activating mutation positive/wild/unknown 30/48/22 %. The median follow-up period was 13.5 months. The median number of treatment cycles was 4 (range 1–18 cycles). The median PFS was 5.2 months (95 % CI 3.0–5.8 months). The median OS was 14.4 months (95 % CI 9.4–21.3 months). The ORR was 8.7 % and DCR was 63.0 %. The grade 3/4 hematological adverse events include 8 patients with leukopenia, 11 with neutropenia, 5 with anemia, and 2 with thrombocytopenia. There were no reports of febrile neutropenia and no treatment-related death was observed.

Conclusion

Treatment with pemetrexed in previously heavily treated Japanese non-squamous NSCLC patients is feasible and shows encouraging activity.     

A retrospective study of S-1 and oxaliplatin combination chemotherapy in patients with refractory pancreatic cancer

Purpose

The aim of this study was to evaluate S-1 and oxaliplatin combination chemotherapy (SOX) in patients with refractory pancreatic cancer (PC).

Methods

Consecutive patients with advanced PC refractory to gemcitabine who were treated with oral S-1 (80 mg/m²) on days 1–14 and intravenous oxaliplatin (100 mg/m²) on day 1 every 3 weeks were studied retrospectively. The primary end point was the objective response rate (ORR). The secondary end points were progression-free survival (PFS), overall survival (OS), the disease control rate (DCR), and safety.

Results

Between March 2009 and October 2011, 30 patients were treated with SOX, with a median of two courses (range 1–8). The ORR and DCR were 10.0 and 50.0 %, respectively. Median PFS and OS were 3.4 months (95 % confidence interval [CI] 1.3–5.3) and 5.0 months (95 % CI 3.4–7.4), respectively. The median PFS and OS were 5.6 and 9.1 months in patients receiving S-1 and oxaliplatin as a second-line treatment. Major grade 3 or 4 adverse events included neutropenia (10.0 %), anemia (3.3 %), and diarrhea (6.7 %).

Conclusions

SOX was well tolerated and moderately effective in patients with refractory PC.