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.

     

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.     

Study of Gefitinib and Pemetrexed as First-Line Treatment in Patients with Advanced Non-Small Cell Lung Cancer Harboring EGFR Mutation

To evaluate the efficacy and safety of a combination regimen of gefitinib and pemetrexed as first-line chemotherapy in advanced EGFR-mutated non-small cell lung cancer (NSCLC) patients. Patients and methods Patients with advanced non-squamous NSCLC harboring asensitive EGFR mutation were included in this study and randomly divided into gefitinib + placebo group and gefitinib + pemetrexed group. Pemetrexed or placebo was administered on day 1 at a dose of 500 mg/m², and gefitinib was sequentially administered on days 2 ~ 16. This treatment regimen was repeated every 3 weeks until disease progression. All investigators and participants were masked to treatment allocation. The overall response rate (ORR) and disease control rate (DCR) of gefitinib + pemetrexed group were higher than that of gefitinib + placebo group but only the difference of DCR between two groups was statistically significant (P < 0.05). The median progression-free survival (PFS) of gefitinib + placebo group and gefitinib + pemetrexed group were 14.0 months vs. 18 months respectively and the difference was statistically significant (P < 0.05). The 2-year PFS rates of gefitinib + pemetrexed group (20.00 %) was higher than that of gefitinib + placebo group (8.89 %) and the difference was statistically significant (P < 0.05). The median overall survival (OS) of gefitinib + placebo group and gefitinib + pemetrexed group were 32.0 months vs. 34 months respectively and the difference was not statistically significant (P > 0.05). The 3-year OS rates of gefitinib + pemetrexed group (44.44 %) was higher than that of gefitinib + placebo group (35.56 %) but the difference was not statistically significant (P > 0.05). Major grade 3 or 4 hematological toxicities included neutropenia, leukopenia and anemia. The main grade 3 or 4 non-hematological toxicities were infection, increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, fatigue, diarrhea and pneumonitis. The difference of toxicities between two groups was not statistically significant (P > 0.05). The combination regimen of gefitinib + pemetrexed used in this study showed a higher ORR and DCR, longer median PFS and acceptable toxicity.     

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).     

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.     

Phase II trial of erlotinib in patients with advanced non-small-cell lung cancer harboring epidermal growth factor receptor mutations: additive analysis of pharmacokinetics

Background

We conducted a phase II trial of erlotinib in patients with advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations and evaluated the relationship between plasma concentration and efficacy of erlotinib.

Methods

Patients who were previously treated but naive to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), with advanced NSCLC harboring EGFR mutations, were enrolled. Erlotinib was given at 150 mg once daily until disease progression. The primary end point was objective response rate (ORR). Plasma trough levels of erlotinib were measured on Days 2 (D2) and 8 (D8) by high-performance liquid chromatography.

Results

In total, 29 patients were enrolled from September 2008 to January 2011. ORR was 61.5 % (95 % confidence interval [CI] 40.57–79.8) of 26 assessable patients. The median progression-free survival (PFS) and overall survival (OS) were 6.3 months and 16.9 months, respectively. Skin rash was observed in 24 patients, mostly at grade 1 or 2. Grade 2 pneumonitis was observed in one patient. We collected blood samples from 16 patients. The median PFS of the high and low D8/D2 ratio group was 11.2 months and 5.7 months, respectively (p = 0.044, hazard ratio = 0.301, 95 % CI 0.094–0.968).

Conclusion

Erlotinib showed an ORR comparable to that seen in previous studies for patients with NSCLC harboring EGFR mutations, although response, the primary end point, did not reach the predetermined threshold level. The D8/D2 ratio of erlotinib plasma trough levels might be a predictive factor for PFS.     

Phase II study of carboplatin and pemetrexed in advanced non-squamous, non-small-cell lung cancer: Kyoto Thoracic Oncology Research Group Trial 0902

Background

Subgroup analyses of randomized studies have consistently shown that pemetrexed is exclusively effective in non-small-cell lung cancer (NSCLC) other than squamous cell carcinoma and the combination of pemetrexed and platinum agents is recommended for first-line chemotherapy in advanced non-squamous NSCLC; however, there have been few prospective studies of a selected population.

Patients and methods

This was a single-arm phase II study of carboplatin and pemetrexed in Japanese patients with chemo-naive advanced non-squamous NSCLC. Patients received six cycles of pemetrexed (500?mg/m²) combined with carboplatin (area under the curve: AUC 6) every 3?weeks. Maintenance chemotherapy with pemetrexed was permitted in patients whose disease did not progress after combination chemotherapy. The primary endpoint was the response rate, and secondary endpoints were safety and survival.

Results

Fifty-one patients were enrolled between November 2009 and March 2011, and 49 patients were evaluable for both safety and efficacy. All but one patient had adenocarcinoma histology. Forty-four (90?%) patients completed four cycles, and 33 (67?%) completed six cycles of chemotherapy. Partial response was achieved in 25 patients (response rate: 51?%) and stable disease in 18 patients (37?%). Median progression-free survival (PFS) and overall survival (OS) were 6.3?months and 24.3?months, respectively. The median PFS and OS were 7.9?months and 24.3?months in patients with epidermal growth factor receptor (EGFR) mutation, and 6.3?months and 21.0?months in patients with EGFR wild type or unknown. There were no statistical differences between EGFR mutants and non-mutants for both PFS (p?=?0.09) and OS (p?=?0.23). Grade 3/4 neutropenia and thrombocytopenia were observed in 16 (33?%) and 9 (18?%) patients, respectively. Non-hematologic toxicities were generally mild, and there were no treatment-related deaths.

Conclusions

The combination of carboplatin and pemetrexed was safe and effective in advanced non-squamous NSCLC. Although the sample size was small, our results indicate that pemetrexed is a key drug for advanced non-squamous NSCLC, irrespective of the EGFR mutation status (UMIN-CTR number 000002451).     

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.     

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 multicenter phase II study of docetaxel, oxaliplatin, and bevacizumab in first-line therapy for unresectable locally advanced or metastatic non-squamous cell histology non-small-cell lung cancer (NSCLC)

Introduction

Platinum-based doublets are standard of care for advanced non-small-cell lung cancer (NSCLC). The combination of docetaxel and oxaliplatin has shown acceptable toxicity and encouraging activity. This phase II study aimed to determine the safety and efficacy of this doublet with bevacizumab as first-line treatment for stage IIIB/IV NSCLC.

Methods

Newly diagnosed patients ≥18 years with histologically proven non-squamous NSCLC and Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2 received six 21-day cycles of docetaxel, oxaliplatin, and bevacizumab followed by single-agent bevacizumab for a total of 1 year. Primary efficacy end point was radiographically documented progression-free survival (PFS); secondary end points included objective response rate (ORR), overall survival (OS), time to treatment failure, and safety.

Results

Fifty-three patients were enrolled. Median age was 62.0 years, 71.7 % male, 79.2 % Caucasian. A total of 88.7 % had stage IV or recurrent disease; 94.3 % adenocarcinoma; and 94.3 % ECOG PS 0 or 1. Efficacy results are as follows: median PFS 5.6 months, ORR 30.2 % (complete response 1.9 %, partial response 28.3 %); 37.7 % stable disease; and OS 14.0 months. At least one adverse event (AE) was reported in all patients (n = 52); 98.1 % of AEs were treatment related. The most common treatment-emergent grade ≥3 AEs were neutropenia (15.4 %), diarrhea (13.5 %), and fatigue (11.5 %). A serious AE was present in 32.7 %; the most common were pneumonia (7.7 %) and abdominal pain (5.8 %). Dehydration, diarrhea, febrile neutropenia, sepsis, and supraventricular tachycardia each occurred in 3.8 %.

Conclusions

The addition of bevacizumab to docetaxel/oxaliplatin is effective with an acceptable safety profile in patients with chemotherapy-naïve advanced NSCLC.     

Phase II gemcitabine and capecitabine combination therapy in recurrent or metastatic breast cancer patients pretreated with anthracycline and taxane

Purpose

We conducted a phase II study evaluating safety and efficacy of combination gemcitabine and capecitabine therapy for metastatic breast cancer patients following anthracycline and taxane treatment in Korea.

Methods

This was a single-arm, non-randomized phase II study. Patients received 1,000 mg/m² gemcitabine intravenously over 30 min on days 1 and 8, and 1,250 mg/m² capecitabine orally twice daily on days 1–14 until disease progression or intolerable toxicity occurred. This regimen was repeated every 3 weeks. The primary outcome assessed was overall response rate [ORR, complete response (CR) + partial response (PR) as the best response], and secondary outcomes were progression-free survival (PFS), overall survival (OS), disease control rate (DCR) [maintenance of CR + PR + stable disease (SD) for at least 3 months], drug toxicity, and predictive factors for response to this regimen.

Results

Of 41 patients, the ORR was 39.0 % (CR 0 %; PR 39.0 %), and DCR was 78.0 % using this chemotherapy. DCR for 6 and 12 months was 68.3 and 26.8 %, respectively. Median PFS was 10.0 months [95 % confidence interval (CI) 7.8–12.1], and median OS was 25.1 months (95 % CI 18.2–32.1). Prominent toxicities were neutropenia and hand–foot syndrome. Most adverse events were well known, relatively moderate, and reversible. Taxane sensitivity [odds ratio (OR) 0.169; 95 % CI 0.034–0.826; P = 0.028] and hepatic metastasis (OR 0.097; 95 % CI 0.017–0.559; P = 0.009) were significantly predictive of response to gemcitabine and capecitabine combination.

Conclusions

This study showed reproducible anticancer activity and tolerable toxicity of gemcitabine and capecitabine combination therapy in recurrent or metastatic Korean breast cancer patients previously treated with anthracycline and taxane.     

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.

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.     

Bevacizumab Plus Pemetrexed Versus Pemetrexed Alone as Maintenance Therapy for Patients With Advanced Nonsquamous Non–Small-cell Lung Cancer: Update From the Swiss Group for Clinical Cancer Research (SAKK) 19/09 Trial

Background

Pemetrexed and bevacizumab as single agents have been approved for maintenance therapy after platinum-based induction in patients with advanced nonsquamous non–small-cell lung cancer. It is currently unknown whether bevacizumab plus pemetrexed is superior to pemetrexed alone.

Randomized Phase 2 Trial of Pharmacodynamic Separation of Pemetrexed and Intercalated Erlotinib Versus Pemetrexed Alone for Advanced Nonsquamous,Non–small-cell Lung Cancer

Background

Pharmacodynamic separation of pemetrexed and erlotinib avoids negative cellular interactions and results in antitumor synergy in erlotinib-resistant non–small-cell lung cancer (NSCLC) cells, independent of EGFR (epidermal growth factor receptor) genotype.

A phase II trial of gefitinib monotherapy in pretreated patients with advanced non-small cell lung cancer not harboring activating EGFR mutations: implications of sensitive EGFR mutation test

Purpose

Efficacy of gefitinib therapy strongly depends on epidermal growth factor receptor (EGFR) mutation status in patients with non-small cell lung cancer (NSCLC). However, cumulative data from many clinical studies demonstrated that some patients with wild-type (WT) EGFR also responded to gefitinib with durable disease control rate (DCR). The aim of this trial was to evaluate the efficacy and toxicity of gefitinib in NSCLC patients with WT EGFR who failed previous chemotherapy.

Patients and methods

Patients with advanced or recurrent NSCLC whose tumors have WT EGFR were eligible. Gefitinib (250 mg/day) was administered until disease progression or unacceptable toxicity occurred. The primary end point was DCR at 8 weeks.

Results

A total of 85 patients (53 men and 32 women; median age, 60 years; range 30–86) were enrolled between October 2010 and May 2013. Seventy-four patients (87.1 %) had adenocarcinoma. Forty-two patients (49.4 %) were treated with gefitinib as second-line chemotherapy. Eleven patients showed partial response, and 21 had stable disease. Thus, objective response rate was 12.9 %, and DCR at 8 weeks was 37.6 %. The median progression-free survival (PFS) and overall survival were 1.9 and 10.9 months, respectively. Skin rash was the most common side effect. It is of note that patients with skin rash of any grade had improved PFS with gefitinib as compared with patients experiencing no skin rash (median PFS: 3.0 vs. 1.7 months, P = 0.004). One patient developed interstitial lung disease (grade 2). Of 11 gefitinib responders, 6 patients were identified as having tumor with activating EGFR mutation by peptide nucleic acid (PNA)-mediated PCR clamping method. Regarding the outcomes of the 79 patients, excluding 6 positive mutations, the response rate was 6.3 %, and DCR at 8 weeks was 31.8 %.

Conclusion

Small proportion of NSCLC patients with the WT EGFR benefits with gefitinib. Optimized diagnosis through more sensitive bioassay could have major consequences in terms of the selection of candidate for EGFR TKI in patients with WT EGFR by direct sequencing.

     

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.     

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.     

Treatment outcomes of gemcitabine alone versus gemcitabine plus platinum for advanced biliary tract cancer: a Korean Cancer Study Group retrospective analysis

Purpose

ABC-02 trial of gemcitabine plus cisplatin combination showed prolongation of overall survival in biliary tract cancer (BTC) patients. In this multicenter retrospective study, we evaluated the treatment outcome of gemcitabine combined with platinum (GP) compared to that of gemcitabine (G) alone in Korean BTC patients.

Methods

One hundred and fifty-one patients with histologically confirmed biliary tract adenocarcinoma were enrolled at nine institutions between July 2003 and May 2011, including 100 treated with GP and 51 treated with G.

Results

With a median follow-up of 7.7 months (range 0.4–38.3 months), the median overall survival (OS) was 12.4 months [95 % confidence interval (CI) 9.4–15.6 months] of the G group, which was not significantly different for the median OS of 11.0 months (95 % CI 9.7–12.3 months) of the GP group (p = 0.599). The median progression-free survival (PFS) was 3.9 months (95 % CI 0.8–7.0 months) in the G group and 3.3 months (95 % CI 2.6–4.0 months) in the GP group (p = 0.504). Overall response rates (ORR) were 18.8 % in G group and 23.9 % in GP group (p = 0.485).

Conclusions

There was no significant difference in ORR, PFS, or OS for patients between the G group and the GP group, which was different from the ABC-02 trial. Therefore, gemcitabine monotherapy and GP combination are both effective regimens for Korean BTC patients.     

Single-agent chemotherapy compared with combination chemotherapy as second-line treatment in extensive-stage small cell lung cancer: a retrospective analysis

Objective

This retrospective analysis evaluates the clinical outcomes of extensive-stage small cell lung cancer (SCLC) patients who received second-line chemotherapy after platinum-based first-line chemotherapy, especially focusing on efficacy and toxicity between single-agent and combination chemotherapy.

Methods

We retrospectively reviewed 193 patients who received second-line chemotherapy for extensive-stage SCLC. Patients relapsing or progressing beyond 90 days were defined as sensitive recurrence patients, and below 90 days as refractory recurrence patients. Survival curves were plotted using the Kaplan–Meier method. The Cox proportional hazard model was used for multivariate analysis.

Results

138 patients received combination chemotherapy and 55 received single-agent treatment. The objective response rate (ORR) was 25.4 % in the combination group and 9.1 % in the single-agent group (p = 0.012). The disease control rate (DCR) was 65.2 and 34.5 %, respectively, (p < 0.001). The progression-free survival (PFS) was 3.80 months in the combination group and 2.13 months in the single-agent group (p = 0.001). In the sensitive recurrence group, the median PFS was 3.80 months in combination group and 3.23 months in single-agent group (p = 0.092). In the refractory recurrence group, the median PFS was 2.83 and 1.30 months, respectively (p = 0.001). The grade III/IV toxicity in single-agent group is much lower than the combination group (56.4 vs. 74.6 %, p = 0.013).

Conclusion

Our retrospective data suggest a potential role of prolonging the PFS for combination treatment in extensive-stage SCLC second-line treatment, especially for the refractory recurrence patients, but with more toxicity as compared to single-agent.