Maintenance therapy with pemetrexed versus docetaxel after induction therapy with carboplatin and pemetrexed in chemotherapy-naïve patients with advanced non-squamous non-small-cell lung cancer: a randomized, phase II study

Purpose

The optimal strategy for maintenance chemotherapy is controversial. We evaluated the efficacy and safety of continuation maintenance with pemetrexed and switch maintenance with docetaxel in advanced non-squamous non-small-cell lung cancer (NSCLC).

Methods

Chemotherapy-naïve patients with non-squamous NSCLC were enrolled in this randomized phase II study. Patients who achieved disease control after four cycles of induction therapy with carboplatin (AUC 6) and pemetrexed (500 mg/m²) were randomized to maintenance therapy with pemetrexed (500 mg/m²) or docetaxel (60 mg/m²). The primary endpoint was survival without toxicity, defined as the time from the initiation of maintenance therapy to the first date of any grade 3/4 toxicity or death due to any cause.

Results

A total of eighty-five patients were enrolled in the induction phase, and 26 patients were assigned to the pemetrexed maintenance therapy and 25 patients were assigned to the docetaxel maintenance therapy. Survival without toxicity was significantly longer in the pemetrexed group (median 20.8 months, 95 % confidence interval (CI) 0.7–not estimable) than in the docetaxel group (median 0.5 months, 95 % CI 0.2–2.0, hazard ratio 0.36, 95 % CI 0.17–0.74).

Conclusions

Continuation maintenance with pemetrexed may be a feasible treatment option for patients with non-squamous NSCLC who have achieved disease control after induction therapy with carboplatin and pemetrexed. Switch maintenance with docetaxel may also be efficacious but frequently causes severe hematologic toxicity.     

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 phase II, randomized, multicenter study to assess the efficacy, safety, and tolerability of zibotentan (ZD4054) in combination with pemetrexed in patients with advanced non-small cell lung cancer

Purpose

This study evaluated overall survival (OS) of patients with advanced non-squamous NSCLC following treatment with the specific endothelin A receptor antagonist, zibotentan in combination with pemetrexed compared with pemetrexed monotherapy.

Methods

In this double-blinded, placebo-controlled study, patients with advanced NSCLC with non-squamous histology who had failed first-line platinum-based chemotherapy were randomized to receive either once-daily zibotentan 10 mg in combination with 3-weekly pemetrexed 500 mg/m² or placebo plus 3-weekly pemetrexed 500 mg/m². OS was calculated as the interval from date of randomization to date of death from any cause. Safety and tolerability were evaluated by recording the incidence of adverse events (AE) according to Common Toxicity Criteria for AE (CTCAE).

Results

Sixty-six patients were randomized and completed the study (zibotentan plus pemetrexed, n = 30; placebo plus pemetrexed, n = 36). At the data cutoff, a total of 44 deaths had occurred, 20 and 24 in the zibotentan and placebo groups, respectively. No significant difference in OS was observed between the zibotentan and placebo treatment groups (HR, 1.13; 80% CI 0.77, 1.67; P = 0.69). The majority of AE were of CTCAE grade 1 or 2, and the most commonly reported AE in both treatment groups was anemia (23 and 25% of patients in the zibotentan and placebo groups, respectively).

Conclusions

There was no survival signal in patients with NSCLC following treatment with zibotentan in combination with pemetrexed. No new issues related to safety for either zibotentan or pemetrexed were identified.     

A phase II randomized trial evaluating gefitinib intercalated with pemetrexed/platinum chemotherapy or pemetrexed/platinum chemotherapy alone in unselected patients with advanced non-squamous non-small cell lung cancer

Current pemetrexed/platinum chemotherapy does not produce a satisfactory therapeutic response in advanced lung cancer patients. The aim of this study was to determine whether the administration of gefitinib, a tyrosine kinase inhibitor (TKI), intercalated with pemetrexed/platinum could improve the efficacy in chemotherapy-naïve patients with advanced non-squamous NSCLC without subsequent gefitinib maintenance therapy. Treatment-naïve patients with stage IIIB or IV NSCLC were randomly assigned to receive pemetrexed (500 mg/m² d1) and either cisplatin (75 mg/m² d1) or carboplatin (AUC = 5 d1) plus gefitinib (250 mg/d on days 3 to 16 of a 3-week cycle) (PC-G) or pemetrexed–platinum (PC) alone. Randomization was stratified according to the tobacco smoking status and EGFR mutational status of the patients. The primary endpoint was the non-progression rate (NPR) at 12 weeks. Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), overall survival (OS), and biosafety. The NPR at 12 weeks was 84.5% for the PC-G treatment arm and 83.1% for the PC treatment arm (P = 0.87). Median PFS was 7.9 months for the PC-G arm and 7.0 months for the PC arm (P = 0.57). The ORR was 50.0% for the PC-G arm and 47.4% for the PC arm (P = 0.78). Median survival was 25.4 mo for the PC-G arm and 20.8 mo for the PC arm (P = 0.54). The incidence of adverse events was similar between the two treatment arms, except for a higher incidence of skin rash with PC-G. Predefined subgroup analyses demonstrated that PC-G significantly increased the PFS compared with the PC regimen in patients with EGFR mutations (P = 0.017). Although gefitinib intercalated with pemetrexed/platinum chemotherapy did not improve the NPR at 12 weeks compared with chemotherapy, an improvement in the PFS for the intercalated treatment arm was seen in the subgroup of patients with EGFR mutations.     

培美曲塞联合铂类一线治疗晚期非鳞非小细胞肺癌的临床观察

背景与目的：晚期肺癌一线化疗有效率仅30%～40%,本研究旨在探讨培美曲塞联合铂类药物(卡铂或顺铂)治疗晚期非鳞非小细胞肺癌(non-small cell lung cancer,NSCLC)的疗效及不良反应。方法：121例非鳞NSCLC患者,给予培美曲塞联合铂类化疗：培美曲塞500 mg/m2第1天,静脉滴注,卡铂300 mg/m2,第1天,静脉滴注,每3周重复;或培美曲塞500 mg/m2,第1天,静脉滴注,顺铂70 mg/m2,第1天,静脉滴注,每3周重复。上述方案连用2~6个周期,至少2个周期评价疗效。主要观察终点是疾病控制率(diseasecontrol rate,DCR),其次是中位无进展生存时间(progression-free survival,PFS)、1年生存率和安全性。结果：全组可评价疗效121例,完全缓解(complete response,CR)1例,部分缓解(partial response,PR)44例,病情稳定(stable disease,SD)50例,疾病进展(progressive disease,PD)26例,客观有效率(objective response rate,ORR)为37.2%(45/121),DCR为78.5%(95/121),PFS为5.2个月(95%CI：4.4~6.0个月),1年生存率为59.0%。其中培美曲塞联合卡铂组ORR为38.3%(23/60),DCR为78.3%(47/60),PFS为5.1个月(95%CI：3.8~6.4个月),1年生存率55.2%;培美曲塞联合顺铂组ORR为36.1%(22/61),DCR为78.7%(48/61),PFS为6.2个月(95%CI：4.3~8.1个月),1年生存率为62.5%。两组之间的ORR、DCR、PFS和1年生存率差异无统计学意义(P＞0.05)。主要不良反应为中性粒细胞和白细胞下降、乏力及胃肠道反应。结论：培美曲塞联合铂类药物一线治疗晚期非鳞NSCLC疗效确切,不良反应发生率低,耐受性较好。     

A phase II study of carboplatin,pemetrexed, and bevacizumab followed by erlotinib and bevacizumab maintenance for non-squamous non-small cell lung cancer with wild-type <Emphasis Type="Italic">EGFR</Emphasis> (HOT1101)

Background

This study evaluated the efficacy and safety of switch maintenance erlotinib and bevacizumab after induction therapy with carboplatin/pemetrexed/bevacizumab for non-squamous non-small cell lung cancer (NSCLC) with wild-type EGFR.

Methods

Enrolled patients had treatment-naïve, advanced non-squamous NSCLC with wild-type EGFR. Carboplatin [area under the curve (AUC) 5.0], pemetrexed (500 mg/m2) and bevacizumab (15 mg/kg) were administered on day 1 every 3 weeks for 4–6 cycles. Maintenance therapy with erlotinib (150 mg/body) on day 1 through 21 plus bevacizumab on day 1 every 3 weeks was continued until disease progression or unacceptable toxicity. The primary endpoint was 6-month progression-free survival (PFS); secondary endpoints included overall survival (OS), overall response rate (ORR), toxicity, and quality of life (QOL).

Results

Fifty-one patients were enrolled between September 2011 and June 2014. The median number of cycles for induction and maintenance therapy was 4 (range 1–6) and 4 (range 1–20). Twenty-nine patients (58%) received maintenance therapy. The 6-month PFS rate was 59.5% [95% confidence interval (CI) 45.0–72.6%]. The ORR was 48.0% (95% CI 34.8–61.5%), and disease control rate was 86.0% (95% CI 73.8–93.0%). The median PFS and OS were 6.5 months (95% CI 5.8–7.2 months) and 21.4 months (95% CI 15.9–26.9 months), respectively. Although grades ≥?3 adverse events were observed in 33 patients (66.0%), most were hematologic; there was no febrile neutropenia. QOL was maintained throughout treatment.

Conclusions

Carboplatin/pemetrexed/bevacizumab followed by erlotinib and bevacizumab maintenance showed modest efficacy and was well tolerated in non-squamous NSCLC patients with wild-type EGFR.

Trial registration

UMIN000005872.

     

Effect of front-line chemotherapy on circulating CK-19 mRNA-positive cells in patients with metastatic breast cancer

Purpose

The incidence of lung cancer in patients with interstitial lung disease (ILD) is higher than in the general population; however, the clinical benefit of chemotherapy and the appropriate regimen for non-small-cell lung cancer (NSCLC) patients with ILD remain unclear. This study was conducted to elucidate the safety and efficacy of palliative chemotherapy with gemcitabine or pemetrexed, both in combination with a platinum agent in NSCLC patients with ILD.

Patients and methods

Patients with advanced or recurrent NSCLC and ILD who received gemcitabine or pemetrexed in combination with a platinum agent as first-line chemotherapy were retrospectively analyzed. Clinical outcomes, including response rate, overall survival (OS), and progression-free survival (PFS), in addition to the acute exacerbation of ILD after chemotherapy were investigated.

Results

Between January 2007 and December 2011, 52 patients were analyzed. The median age at chemotherapy was 67. Thirty-two patients (61.5 %) had adenocarcinoma histology. With respect to the types of ILD, idiopathic interstitial pneumonia (IIP) and non-IIP were observed in 42 (80.8 %) and 10 (19.2 %) patients, respectively. The FEV1 level was less than 80 % of the predicted value in 15 of the 41 patients in whom it was measured. The overall response rate was 42.3 % (95 % CI 28.8–55.9), and the median PFS was 5.4 months (95 % CI 4.6–6.2). The median OS was 7.9 months (95 % CI 5.5–10.3), and the 1-year survival rate was 31.7 % (95 % CI 19.0–44.4). Eight patients (15.4 %) died within 3 months of first-line chemotherapy. Multivariate analysis demonstrated that a heavy smoking history (40 or more pack-year smoking history) was an independent adverse prognostic factor for OS. An acute exacerbation of ILD (AE-ILD) caused by first-line chemotherapy was noted in 5.8 % of patients.

Conclusion

Our results suggest that gemcitabine or pemetrexed in combination with platinum agents could be a feasible option for advanced NSCLC with ILD with some risk of AE-ILD or early death. To establish the efficacy of palliative chemotherapy for patients with NSCLC and ILD, further well-controlled prospective studies are needed.     

Is there any predictor for clinical outcome in EGFR mutant NSCLC patients treated with EGFR TKIs?

Background

Tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) have demonstrated some dramatic response rate and prolonged progression-free survival (PFS) in advanced non-small-cell lung cancer (NSCLC) patients with activating EGFR mutation. However, PFS and overall survival (OS) among those patients who were treated with EGFR TKIs are inconsistent and unpredictable. In this study, we evaluated predictors of clinical outcome in EGFR mutant NSCLC patients treated with EGFR TKIs.

Methods

A total of 148 patients who had metastatic or recurrent NSCLC with activating EGFR mutation treated with either erlotinib or gefitinib as a first-line (n = 10) and a second-line or more treatment (n = 138) were retrospectively reviewed.

Results

The median follow-up duration was 21.9 months (range, 1.1–62.5). The median PFS and OS for a total 148 patients were 10.6 months (95 % CI 9.0–12.2) and 21.8 months (95 % CI 18.5–25.1), respectively. The survival outcomes were similar between the first-line and second-line or more line of treatment of EGFR TKIs (P = 0.512 for PFS, P = 0.699 for OS). Although a high number of metastasis sites (3–6 vs. 1–2) were associated with shorter PFS and OS (median PFS 9.9 vs. 11.9 months, P = 0.019; median OS 16.4 vs. 22.2 months, P = 0.021, respectively) in univariate analysis, but not in multivariate analysis. According to the clinical and molecular markers by multivariate analysis, there were no significant differences in PFS. When PFS was dichotomized by median 11 months for 105 patients treated with EGFR TKIs as second-line therapy, no significant differences in any clinical or molecular features were found between longer PFS and shorter PFS groups.

Conclusions

Despite the inconsistencies in PFS among EGFR mutant patients treated with EGFR TKIs, no significant differences of clinical features were noted, thereby suggesting a need for more understanding of the heterogeneity of underlying biology.     

Phase II study of S-1 monotherapy in patients with previously treated, advanced non-small-cell lung cancer

Background

In this phase II clinical trial, we evaluated the efficacy and safety of S-1 monotherapy in patients with previously treated advanced non-small-cell lung cancer (NSCLC). We also measured plasma concentrations of 5-fluorouracil (5-FU) and 5-chloro-2,4-dihydroxypyridine components of S-1 and examined correlation with effectiveness and toxicity.

Methods

S-1 was given orally at a dose of 80?mg/m²/day for 14 consecutive days, followed by a 7-day rest period. This treatment course was repeated until disease progression or intolerable toxicity.

Results

We enrolled 30 patients. The response rate was 26.7% (8/30), and the disease control rate was 70% (21/30). Median progression-free survival (PFS) was 3.1?months, and median overall survival (OS) was 11.2?months. Mutations in the epidermal growth factor receptor (EGFR) gene were analyzed in 27 patients. The response rate was higher in patients with mutant EGFR (50.0%) than in those with wild-type EGFR (11.8%, P?=?0.0288). Median PFS was 4.8 and 2.5?months (P?=?0.038), and median OS was 22.4 and 8.4?months (P?=?0.071). There was no grade 4 toxicity in this study. Five patients had grade 3 non-hematologic toxicity, and there was a trend toward higher plasma concentrations of 5-FU in those patients than in another patients.

Conclusions

S-1 monotherapy is effective and well-tolerated treatment for previously treated advanced NSCLC.     

Pemetrexed plus carboplatin versus pemetrexed in pretreated patients with advanced non-squamous non-small-cell lung cancer: treating the right patients based on individualized treatment effect prediction

BackgroundTranslating results from randomized clinical trials (RCTs) to individual patients in clinical practice is challenging, as treatment effects can vary substantially among individuals. Data from RCTs can be used for individualized treatment effect prediction, to identify patients who benefit from specific treatments. In this study, we developed and validated a prediction model for estimating absolute treatment effect of pemetrexed plus carboplatin versus single-agent pemetrexed in the second-line treatment of non-squamous non-small-cell lung cancer (NSCLC).Patients and methodsUsing data of relapsed patients with advanced non-squamous NSCLC from the NVALT-7 trial, a Weibull model for prediction of gain in median progression-free survival (PFS) by pemetrexed–carboplatin was derived based on patient and tumor characteristics. The model was externally validated in the GOIRC 02-2006 trial. The applicability of the model for guiding clinical decision-making was evaluated using decision curve analysis.ResultsA wide distribution of predicted gain in median PFS by pemetrexed–carboplatin over pemetrexed was found, with a median of 0.7 months (interquartile range: -0.1 to 1.5 months). Patients who benefited most included women, those with stage IV, high body mass index and/or adenocarcinoma. External validation showed satisfactory calibration and moderate discrimination (C-index: 0.61, 95% confidence interval 0.56–0.67). Decision curve analysis confirmed that the model adequately identified patients who benefit from pemetrexed–carboplatin, as prediction-based treatment led to improvement in net benefit with regard to PFS and overall survival when assuming a treatment threshold of 0–5 months gain in PFS, compared with other treatment strategies.ConclusionsThe effects of pemetrexed–carboplatin can be predicted for individual patients based on routinely available patient and tumor characteristics. There is important heterogeneity in the effects on PFS of pemetrexed–carboplatin versus pemetrexed in pretreated patients with advanced non-squamous NSCLC. Individualized prediction of treatment effect could be used to guide shared decision-making by discriminating patients who benefit most, to improve clinical outcome.Clinical Trial numbersNVALT-7: ISRCTN38269072 (ISRCTN registry), GOIRC 02-2006: NCT00786331 (clinicaltrials.gov).     

Phase II study of pemetrexed as first-line treatment in elderly (≥75) non-squamous non-small-cell lung cancer: Kyoto Thoracic Oncology Research Group Trial 0901

Background

Single-agent chemotherapy with third-generation non-platinum agents, such as docetaxel, vinorelbine, is a standard therapeutic option for elderly patients with non-small-cell lung cancer (NSCLC). Subset analysis of a previous phase III study comparing pemetrexed with docetaxel in the second-line setting showed the superiority of pemetrexed in an elderly (≥70) population in both efficacy and toxicity.

Patients and methods

This was a single-arm phase II study of pemetrexed in elderly (≥75) Japanese patients with advanced non-squamous NSCLC. Patients received four cycles of pemetrexed (500 mg/m²) every 3 weeks. The primary endpoint was the response rate, and secondary endpoints were safety and survival.

Results

Twenty-eight patients were enrolled between January 2010 and April 2012. The median age of the patients was 77 years (range 75–88). All but one patient had adenocarcinoma histology. The median number of chemotherapy cycles administered was 4 (range, 1–12). Seventeen (60 %) patients completed four cycles of chemotherapy. Partial response was achieved in 7 patients (response rate: 25 %) and stable disease in 11 patients (disease control rate: 64 %). Median progression-free survival and overall survival were 3.3 and 17.5 months, respectively. Grade 3/4 neutropenia and thrombocytopenia were observed in 8 patients (29 %) and 2 (7 %), respectively. Non-hematologic toxicities were generally mild, and there were no treatment-related deaths.

Conclusions

Although this study did not meet our primary endpoint, pemetrexed showed favorable antitumor activity with mild toxicity in elderly patients with non-squamous NSCLC. Further investigations of pemetrexed in this population are warranted (UMIN-CTR number, 000002452).     

Combination therapy consisting of gemcitabine, carboplatin, and docetaxel as an active treatment for advanced urothelial carcinoma

Background

To evaluate the efficacy and toxicity of a combination chemotherapy consisting of gemcitabine, carboplatin, and docetaxel (GCD) in patients with advanced urothelial carcinoma (UC) as a phase II trial.

Materials and methods

Patients with metastatic or locally advanced unresectable UC were eligible for this trial. All enrolled patients were considered to be “unfit??for cisplatin-based chemotherapy, or to have methotrexate, vinblastine, doxorubicin, cisplatin (MVAC)-refractory UC. The chemotherapy regimen consisted of gemcitabine 1000?mg/m² on days 1 and 8, and carboplatin (with a target area under the curve of 5) and docetaxel 70?mg/m² on day 1; this was repeated every 21?days.

Results

Thirty-five patients were enrolled, with a median age of 68?years. A total of 89 cycles were administered (median, 2 cycles). Major toxicities were Grade 3/4 neutropenia in 28 (80.0%) patients and Grade 3/4 thrombocytopenia in 18 (51.5%). An objective response rate (ORR) was 11 of 21 patients (52.4%), including a complete response in 1 (4.8%). The median overall survival (OS) was 13.1?months (1-year survival rate, 60%) and the median progression-free survival (PFS) was 5.0?months. Among 16 patients who had previously received MVAC, the ORR, the median PFS, the median OS and 1-year survival rate was 56.3%, 5.0?months, 12.6?months and 54%, respectively.

Conclusions

GCD chemotherapy is active and well tolerated as a first- or second-line therapy for patients with advanced UC. Response rate, duration and survival did not differ between those with and without a history of MVAC treatment.     

Carboplatin plus pemetrexed for platinum-pretreated, advanced non-small cell lung cancer: a retrospective study with pharmacogenetic evaluation

Purpose

In the present study, the combination of carboplatin (CBDCA) plus pemetrexed (PMX) for the treatment of patients with platinum-pretreated, pemetrexed-na?ve, advanced non-small cell lung cancer (NSCLC) was investigated. Also, single nucleotide polymorphisms (SNPs) at the XRCC3, XPD, ERCC1, GARFT, DHFR, and TS genes were investigated.

Methods

Eighty patients treated with CBDCA/PMX at two Italian institutions were evaluable. Of these, 73 patients had blood samples collected for pharmacogenetic evaluation.

Results

Overall, the median age was 59?years (26?C78), 59 patients (73.7%) had a performance status of 0, and 34 patients (42.5%) had stage IIIB disease. Thirty-eight patients (47.5%) had responded to prior first-line platinum-based therapy. Study treatment resulted into one complete and 33 partial responses for an overall response rate of 42.5%. The disease control rate was 77.5%. The median progression-free survival (PFS) and overall survival (OS) were 5.8?and 17.4?months, respectively. Responders achieved a significant longer PFS and OS versus non-responders (P?=?0.007 and P?=?0.003, respectively). The only grade 3?C4 adverse event occurring in more than 5.0% of patients was neutropenia (6 patients, 7.5%). No statistically significant association was noted between polymorphisms of the genes analyzed and clinical outcome.

Conclusions

In patients with platinum-pretreated, advanced NSCLC and favorable clinical prognostic factors, treatment with CBDCA/PMX is associated with a good clinical outcome and toxicity profile. None of the SNPs analyzed was found to be a useful predictor of treatment efficacy.     

Retrospective efficacy and safety analyses of erlotinib,pemetrexed, and docetaxel in EGFR-mutation-negative patients with previously treated advanced non-squamous non-small-cell lung cancer

ObjectiveSeveral guidelines recommend erlotinib, pemetrexed, or docetaxel for second-line chemotherapy in patients with advanced non-squamous non-small-cell lung cancer (NSCLC). The aim of this study was to retrospectively evaluate the efficacy of erlotinib, pemetrexed, and docetaxel in epidermal growth factor receptor (EGFR) mutation-negative patients with previously treated advanced non-squamous NSCLC.Materials and methodsWe analyzed the efficacy of these agents in patients with previously treated advanced non-squamous NSCLC who had EGFR wild-type tumors, performance status (PS) of 0, 1, or 2 and received erlotinib, pemetrexed, or docetaxel between December 2007 and September 2011. Variability among patient backgrounds was evaluated using propensity scores to assess comparability. The efficacy of these agents was evaluated in patient subgroups with low variability.ResultsThe propensity scores showed that the backgrounds of the groups that received second-line therapy with each agent had low variability and were adequate for comparison. Patients were divided into the PS0/1 and PS2 groups for analysis. The median progression-free survival (PFS) in patients treated with erlotinib was 2.8 months in the PS0/1 group, as compared with 1.0 month in the PS0/1/2 group and 0.90 months in the PS2 group. PFS in PS0/1 patients who received erlotinib was comparable to that in PS0/1 patients who received pemetrexed (2.5 months) or docetaxel (1.9 months). Overall survival (OS) in erlotinib-, pemetrexed-, and docetaxel-treated PS0/1 patients was 16.1, 7.4 and 10.0 months, respectively. The study had limited power to detect differences in PFS and OS because of the small sample size.ConclusionsErlotinib appears to be a useful second-line option in PS0/1 patients with EGFR mutation-negative advanced non-squamous NSCLC given its mild adverse effects. The results should be carefully interpreted because of the small sample size, limited power, and retrospective nature of the study.     

Efficacy and Safety of Onartuzumab in Combination With First-Line Bevacizumab- or Pemetrexed-Based Chemotherapy Regimens in Advanced Non-Squamous Non–Small-Cell Lung Cancer

Background

Onartuzumab is a monovalent monoclonal antibody that binds with the extracellular domain of the MET receptor. Given the role of MET in non–small-cell lung cancer (NSCLC), we investigated whether onartuzumab added to first-line chemotherapy efficacy in non-squamous NSCLC.

Efficacy of EGFR tyrosine kinase inhibitors for non-adenocarcinoma NSCLC patients with EGFR mutation

Purpose

The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) gefitinib and erlotinib have shown dramatic response rate (RR) and significant prolongation of progression-free survival (PFS) in non-small-cell lung cancer (NSCLC) patients with EGFR mutation. Since only a few patients with non-adenocarcinoma histology have been enrolled in clinical trials, the efficacy of EGFR TKIs in non-adenocarcinoma NSCLC patients with EGFR mutation has not yet been fully determined.

Methods

We retrospectively analyzed clinical outcomes, including RR, PFS, and OS, in patients who were treated with the EGFR TKIs gefitinib or erlotinib and compared the results with those of adenocarcinoma patients with EGFR mutation and non-adenocarcinoma patients with wild-type EGFR.

Results

Among 250 patients with non-adenocarcinoma of the lung who underwent EGFR mutation genotyping, 21 were found to have an EGFR mutation (8.4?%). Twelve of the 21 patients were treated with the EGFR TKIs gefitinib (n?=?6) or erlotinib (n?=?6). The most common mutation was exon 19 deletion (n?=?7). The RR and disease control rate for 12 patients receiving EGFR TKIs were 50 and 75?%, respectively. The median PFS was 3.67?months (95?% CI: 1.34?C5.99), which was significantly lower than that of 269 adenocarcinoma patients with EGFR mutation (13.53?months) but better than that of 32 non-adenocarcinoma patients with wild-type EGFR (1.83?months) who were treated with EGFR TKIs.

Conclusions

The results of this study show that the EGFR mutation rate in Korean patients with non-adenocarcinoma of the lung is relatively high and that the clinical outcomes of EGFR TKIs are modest.     

Maintenance therapy with pemetrexed and bevacizumab versus pemetrexed monotherapy after induction therapy with carboplatin,pemetrexed, and bevacizumab in patients with advanced non-squamous non small cell lung cancer

ObjectivesSingle agent maintenance therapy is widely accepted for advanced non-squamous non small cell lung cancer (NSCLC). However, there is no consensus on the initial and maintenance phase regimens, and the clinical benefit of adding bevacizumab to cytotoxic drugs in the maintenance phase remains unclear.MethodsChemotherapy-naïve patients with non-squamous NSCLC were randomly assigned to maintenance therapy with pemetrexed and bevacizumab or pemetrexed alone, after achieving disease control after four cycles of induction therapy with carboplatin (area under the curve = 6), pemetrexed (500 mg/m²), and bevacizumab (15 mg/kg). The primary end-point was 1-year progression-free survival (PFS) rate.ResultsOne hundred ten patients were enrolled in the study, with 55 patients assigned to the two groups. The mean 1-year PFS rate was 43.9% (95% confidence interval [CI]: 29.6–59.2%) in the combination maintenance group and 35.2% (95% CI: 22.1–51.0%) in the pemetrexed maintenance group, and the difference was not significant (p = 0.433). Median PFS measured from enrolment was 11.5 months (95% CI: 7.1–19.0) in the combination maintenance group and 7.3 months (95% CI: 5.7–14.1, hazard ratio: 0.73, 95% CI: 0.44–1.19, log-rank p = 0.198) in the pemetrexed maintenance group. Nasal haemorrhage, hypertension, and proteinuria were significantly more frequent in the combination maintenance group, but they were mild and tolerable.ConclusionBoth maintenance therapy with pemetrexed alone and pemetrexed and bevacizumab in combination were feasible in patients with non-squamous NSCLC who have achieved disease control after induction therapy with carboplatin, pemetrexed, and bevacizumab. According to the selection design, differences in the superiority between these maintenance therapies were not demonstrated.     

The multimodal management of locally advanced N2 non-small cell lung cancer: is there a role for surgical resection? A single institution’s experience

Background

The management of operable locally advanced N2 non-small cell lung cancer (NSCLC) is a controversial topic. Concurrent chemoradiation (CT-RT) is considered the standard of care for inoperable or unresectable patients, but the role of trimodality treatment remains controversial. We present our institution??s experience with the management of stage III (N2) NSCLC patients, analyzing whether the addition of surgery improves survival when compared with definitive CT-RT alone.

Methods

From 1996 to 2006, 72 N2 NSCLC patients were treated. Thirty-four patients received cisplatin-based induction chemotherapy, followed by paclitaxel-cisplatin CT-RT, and 38 patients underwent surgery preceded by induction and/or followed by adjuvant therapy. Survival curves were estimated by Kaplan?CMeier analysis, and the differences were assessed with the log-rank test.

Results

Most of the patients (87?%) were men. The median age was 59?years. A statistically significant association between T3?CT4c and definitive CT-RT as well as between T1?CT2c and surgery was noted (p?<?0.0001). After a median follow-up period of 35?months, the median overall survival (OS) was 42?months for the surgery group versus 41?months for the CT-RT patients (p?=?0.590). The median progression-free survival (PFS) was 14?months after surgery and 25?months after CT-RT (p?=?0.933). Responders to radical CT-RT had a better OS than non-responders (43 vs. 17?months, respectively, p?=?0.011). No significant differences were found in the OS or PFS between the pN0 [14 (37.8?%) patients] and non-pN0 patients at thoracotomy. Three treatment-related deaths (7.8?%) were observed in the surgical cohort and none in the CT-RT group.

Conclusions

The addition of surgery did not render a median OS or PFS benefit when compared with CT-RT alone in our series of stage III-N2 NSCLC patients, in accordance with previously published data. However, responses to CT-RT had a greater impact in terms of OS and PFS. Although the patients selected for management including surgery showed a favorable T clinical staging in comparison to patients exclusively treated with definitive CT-RT, similar survival outcomes were found.     

Combination of chemotherapy and gefitinib as first‐line treatment for patients with advanced lung adenocarcinoma and sensitive EGFR mutations: A randomized controlled trial

To explore the optimal treatment strategy for patients who harbor sensitive EGFR mutations, a head‐to‐head study was performed to compare chemotherapy and gefitinib in combination or with either agent alone as first‐line therapy, in terms of efficacy and safety. A total of 121 untreated patients with advanced lung adenocarcinoma who harbored sensitive EGFR mutations were randomly assigned to receive gefitinib combined with pemetrexed and carboplatin, pemetrexed plus carboplatin or gefitinib alone. The progression‐free survival (PFS) of patients in the combination group (17.5 months, 95% CI, 15.3–19.7) was longer than that of patients in the chemotherapy group (5.7 months, 95% CI, 5.2–6.3) or gefitinib (11.9 months, 95% CI, 9.1–14.6) group. The (hazard ratios) HRs of PFS for the combination group vs. chemotherapy and gefitinib groups were 0.16 (95% CI, 0.09–0.29, p < 0.001) and 0.48 (95% CI, 0.29–0.78, p = 0.003), respectively. The overall response rate (ORR) in the combination therapy group, chemotherapy group and the gefitinib group was 82.5%, 32.5% and 65.9%, respectively. The combinational strategy resulted in longer overall survival (OS) than chemotherapy (HR = 0.46, p = 0.016) or gefitinib (HR = 0.36, p = 0.001) alone. Our finding suggested that treatment with pemetrexed plus carboplatin combined with gefitinib could provide better survival benefits for patients with lung adenocarcinoma harboring sensitive EGFR mutations.