Gefitinib vs. chemotherapy as first-line therapy in advanced non-small cell lung cancer: meta-analysis of phase III trials

Background

Gefitinib is an oral tyrosine kinase inhibitor against the epidermal growth factor receptor (EGFR). It has been shown to be active in patients with advanced non-small cell lung cancer (NSCLC) whose tumors contain EGFR mutations.

Methods

We performed a meta-analysis of four randomized studies that compared gefitinib with chemotherapy in the first-line treatment of patients with advanced NSCLC: IPASS, North-East Japan, West Japan and first-SIGNAL studies. Patients were selected either on the basis of known EGFR mutations or based on clinicopathologic criteria - non-smokers with adenocarcinomas - associated with increased likelihood of EGFR mutations.

Results

Nearly 2000 patients were enrolled on these four trials. Median ages ranged from 57 to 64 years. Seventy-six percent were women and 86% were non-smokers. Overall, gefitinib was associated with significantly less toxicity than chemotherapy and improved quality-of-life. Gefitinib also produced higher response rates in the EGFR mutation-positive patients (72% vs. 38%, odds ratio 4.04, p < 10⁻¹⁵), as well as improved progression-free survival (PFS; hazard ratio 0.45, p < 10⁻¹⁶). Overall survival (OS) was not significantly different between treatment groups (p = 0.35).

Conclusions

This meta-analysis confirms the results of each individual study and narrows the confidence intervals of these results. In patients with known EGFR mutations or whose tumors are likely to harbor a mutation, upfront gefitinib or chemotherapy are associated with similar OS. Gefitinib is associated with less fatigue, myelosuppression and nausea than chemotherapy (but produces more skin rash, diarrhea and pneumonitis). Patients receiving gefitinib have improved quality-of-life compared to those receiving chemotherapy, making it an appropriate first-line choice.     

Randomised phase II study of axitinib or bevacizumab combined with paclitaxel/carboplatin as first-line therapy for patients with advanced non-small-cell lung cancer

BackgroundEfficacy and safety of first-line axitinib/paclitaxel/carboplatin versus bevacizumab/paclitaxel/carboplatin in advanced non-squamous non-small-cell lung cancer (NSCLC) was evaluated.Patients and methodsPatients with stage IIIB/IV disease stratified by adjuvant therapy and gender were randomised 1 : 1 to axitinib (5 mg twice daily) or bevacizumab [15 mg/kg every 3 weeks (Q3W)], both with paclitaxel (200 mg/m² Q3W)/carboplatin (AUC 6 mg min/ml Q3W).ResultsThe trial was discontinued after preliminary analysis. Median progression-free survival (primary end point) for axitinib (N = 58) and bevacizumab (N = 60), respectively, was 5.7 and 6.1 months [hazard ratio (HR) 1.09, 95% confidence interval (CI) 0.68–1.76; one-sided stratified P = 0.64]; median overall survival was 10.6 and 13.3 months (HR 1.12, 95% CI 0.74–1.69; one-sided stratified P = 0.70). Objective response rates (95% CI) were 29.3% (18.1–42.7) and 43.3% (30.6–56.8), respectively; risk ratio 0.676 (95% CI 0.41–1.11; one-sided stratified P = 0.94). The most common grade 3/4 adverse events included neutropenia (28% versus 20%), fatigue (14% versus 7%), and hypertension (14% versus 5%). Patient-reported outcomes based on the EORTC QLQ-C30 were similar between arms.ConclusionsIn patients with advanced non-squamous NSCLC, axitinib/paclitaxel/carboplatin did not improve efficacy versus bevacizumab/paclitaxel/carboplatin, and was less well tolerated.     

Clinical outcome for EML4-ALK-positive patients with advanced non-small-cell lung cancer treated with first-line platinum-based chemotherapy

BackgroundThe EML4-ALK fusion oncogene represents a recently identified molecular target in a subset of patients with non-small-cell lung cancer (NSCLC). Limited data have been available, however, on the outcome of first-line platinum-based chemotherapy in patients with EML4-ALK-positive advanced NSCLC who have not been treated with an ALK kinase inhibitor.Patients and methodsThe efficacy of platinum-based chemotherapy was compared between patients with advanced nonsquamous NSCLC who harbor EML4-ALK and those who harbor EGFR mutations and those with neither molecular abnormality.ResultsAmong 200 patients with advanced nonsquamous NSCLC, 18 (9.0%) were positive for EML4-ALK, 31 (15.5%) harbored EGFR mutations, and 151 (75.5%) were wild type for both abnormalities. Platinum-based combination chemotherapy showed similar efficacies in the EML4-ALK, EGFR mutation, and wild-type cohorts in terms of response rate and progression-free survival, and overall survival in the EML4-ALK cohort closely resembled that in the wild-type cohort. Within the EML4-ALK cohort, patients with variants 1 or 3 of the fusion gene were predominant and did not appear to differ in their sensitivity to the platinum-based regimens.ConclusionPatients with EML4-ALK-positive advanced NSCLC manifest an aggressive clinical course similar to that of those with wild-type tumors if the effective targeted therapy is not instituted.     

Gefitinib compared with systemic chemotherapy as first-line treatment for chemotherapy-naive patients with advanced non-small cell lung cancer: a meta-analysis of randomised controlled trials

To define the efficacy of gefitinib in chemotherapy-naive patients with advanced non-small cell lung cancer, we carried out a meta-analysis of randomised controlled trials. Medline, Embase, the Cochrane controlled trials register and the Science Citation Index were searched. Seven trials were identified, covering a total of 4656 subjects. As compared with chemotherapy, gefitinib was effective in the selected patients: the corresponding summary hazard ratios (gefitinib versus chemotherapy) for progression-free survival were 0.43 (0.32, 0.58) (P < 0.001) for the subgroup of patients with epidermal growth factor receptor (EGFR) mutant treated with gefitinib monotherapy, 0.71 (0.60, 0.83) (P < 0.001) for the subgroup of patients with lung adenocarcinoma; but was detrimental for the patients without EGFR mutant treated by gefitinib monotherapy [hazard ratio = 2.16 (1.17, 3.99), P = 0.01]. Significantly improved survival was found in the gefitinib group compared with the control in the subgroup of patients with lung adenocarcinoma [hazard ratio = 0.89 (0.81, 0.99); P = 0.03], but not found in the subgroup of patients with EGFR mutant [hazard ratio = 0.87 (0.68, 1.12); P = 0.28]. In conclusion, first-line treatment with gefitinib conferred prolonged progression-free survival than treatment with systemic chemotherapy in a molecularly or histologically defined population of patients with non-small cell lung cancer, and improved survival in the subgroup of patients with lung adenocarcinoma.     

Cilengitide combined with cetuximab and platinum-based chemotherapy as first-line treatment in advanced non-small-cell lung cancer (NSCLC) patients: results of an open-label,randomized, controlled phase II study (CERTO)

BackgroundThis multicentre, open-label, randomized, controlled phase II study evaluated cilengitide in combination with cetuximab and platinum-based chemotherapy, compared with cetuximab and chemotherapy alone, as first-line treatment of patients with advanced non-small-cell lung cancer (NSCLC).Patients and methodsPatients were randomized 1:1:1 to receive cetuximab plus platinum-based chemotherapy alone (control), or combined with cilengitide 2000 mg 1×/week i.v. (CIL-once) or 2×/week i.v. (CIL-twice). A protocol amendment limited enrolment to patients with epidermal growth factor receptor (EGFR) histoscore ≥200 and closed the CIL-twice arm for practical feasibility issues. Primary end point was progression-free survival (PFS; independent read); secondary end points included overall survival (OS), safety, and biomarker analyses. A comparison between the CIL-once and control arms is reported, both for the total cohorts, as well as for patients with EGFR histoscore ≥200.ResultsThere were 85 patients in the CIL-once group and 84 in the control group. The PFS (independent read) was 6.2 versus 5.0 months for CIL-once versus control [hazard ratio (HR) 0.72; P = 0.085]; for patients with EGFR histoscore ≥200, PFS was 6.8 versus 5.6 months, respectively (HR 0.57; P = 0.0446). Median OS was 13.6 for CIL-once versus 9.7 months for control (HR 0.81; P = 0.265). In patients with EGFR ≥200, OS was 13.2 versus 11.8 months, respectively (HR 0.95; P = 0.855). No major differences in adverse events between CIL-once and control were reported; nausea (59% versus 56%, respectively) and neutropenia (54% versus 46%, respectively) were the most frequent. There was no increased incidence of thromboembolic events or haemorrhage in cilengitide-treated patients. &agr;v&bgr;3 and &agr;v&bgr;5 expression was neither a predictive nor a prognostic indicator.ConclusionsThe addition of cilengitide to cetuximab/chemotherapy indicated potential clinical activity, with a trend for PFS difference in the independent-read analysis. However, the observed inconsistencies across end points suggest additional investigations are required to substantiate a potential role of other integrin inhibitors in NSCLC treatment.Clinical trial registration ID numberNCT00842712.     

Postprogression survival for first-line chemotherapy of patients with advanced non-small-cell lung cancer

BackgroundGiven the growing number of drugs available for non-small-cell lung cancer (NSCLC), an effect of first-line chemotherapy on overall survival (OS) might be confounded by subsequent therapies. We examined the relation between postprogression survival (PPS) and OS in phase III trials of first-line chemotherapy for advanced NSCLC.Patients and methodsA literature search identified 69 trials that were published during the past decade. We partitioned OS into progression-free survival (PFS) and PPS and evaluated the relation between OS and either PFS or PPS. We also examined whether any association might be affected by the year of completion of trial enrollment.ResultsThe average PPS was longer in recent trials than in older trials (6.5 versus 4.4 months, P < 0.0001). For all trials, PPS was strongly associated with OS (r = 0.82), whereas PFS was moderately associated with OS (r = 0.43). The correlation between OS and PPS in recent trials was stronger than that in older trials (r = 0.89 and 0.66).ConclusionsOur findings indicate that, especially for recent trials, PPS is highly associated with OS in first-line chemotherapy for advanced NSCLC, whereas PFS is only moderately associated with OS.     

Mistletoe as complementary treatment in patients with advanced non-small-cell lung cancer treated with carboplatin-based combinations: A randomised phase II study

IntroductionMistletoe preparations, such as iscador, are common complementary medications. This randomised phase II study of iscador combined with carboplatin-containing regimens was conducted in chemotherapy-naïve advanced non-small-cell lung cancer (NSCLC) patients to assess its influence on chemotherapy-related side-effects and QoL.MethodsPatients with advanced NSCLC were randomised to receive chemotherapy alone or chemotherapy plus iscador thrice weekly until tumour progression. Chemotherapy consisted of 21-day cycles of carboplatin combined with gemcitabine or pemetrexed.ResultsSeventy-two patients (control: 39; iscador: 33) were enrolled in the study. Most (65%) were in stage IV, and 62% had squamous histology. Median overall survival in both groups was 11 months. Median TTP was 4.8 months for the controls and 6 months in the iscador arm (p = NS). Differences in grade 3–4 haematological toxicity were not significant but more control patients had chemotherapy dose reductions (44% versus 13%, p = 0.005), grade 3–4 non-haematological toxicities (41% versus 16%, p = 0.043) and hospitalisations (54% versus 24%, p = 0.016).ConclusionNo effect of iscador could be found on quality of life or total adverse events. Nevertheless, chemotherapy dose reductions, severe non-haematological side-effects and hospitalisations were less frequent in patients treated with iscador, warranting further investigation of iscador as a modifier of chemotherapy-related toxicity.     

Prospective randomised phase II study of docetaxel versus paclitaxel administered weekly in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy.

BACKGROUND: Docetaxel and paclitaxel have activity in the second-line treatment of non-small-cell lung cancer (NSCLC), and can be administered as weekly schedules. This phase II randomised study was designed to test the efficacy and toxicity of both taxanes in patients with NSCLC previously treated with platinum-based chemotherapy. PATIENTS AND METHODS: Patients (n = 71) with documented NSCLC were randomised to receive docetaxel (n = 35 patients; 36 mg/m(2)) or paclitaxel (n = 36 patients; 80 mg/m(2)) as a 1 h weekly infusion for 6 weeks followed by a 2-week rest. The cycles were repeated until disease progression or non-acceptable toxicities occurred. RESULTS: Treatment achieved partial response of one versus five patients, median time-to-progression of 74 versus 68 days, and overall survival of 184 versus 105 days, with docetaxel and paclitaxel, respectively. The most common non-haematological toxicities were (docetaxel versus paclitaxel): grade 3/4 pulmonary toxicity in seven versus one patient; grade 2/3 diarrhoea in nine versus five; and grade 3/4 haematological toxicities occurred in two versus four patients. There were no treatment-related deaths. CONCLUSIONS: Docetaxel and paclitaxel administered weekly have discrete efficacy in patients with NSCLC previously treated with platinum-based chemotherapy. The higher non-haematological toxicity of docetaxel, particularly pulmonary toxicity and diarrhoea, is of concern and warrants further investigation.     

A phase III randomized trial of adding topical nitroglycerin to first-line chemotherapy for advanced nonsmall-cell lung cancer: the Australasian lung cancer trials group NITRO trial

BackgroundWe sought to determine whether the substantial benefits of topical nitroglycerin with first-line, platinum-based, doublet chemotherapy in advanced nonsmall-cell lung cancer (NSCLC) seen in a phase II trial could be corroborated in a rigorous, multicenter, phase III trial.Patients and methodsPatients starting one of five, prespecified, platinum-based doublets as first-line chemotherapy for advanced NSCLC were randomly allocated treatment with or without nitroglycerin 25 mg patches for 2 days before, the day of, and 2 days after, each chemotherapy infusion. Progression-free survival (PFS) was the primary end point.ResultsAccrual was stopped after the first interim analysis of 270 events. Chemotherapy was predominantly with carboplatin and gemcitabine (79%) or carboplatin and paclitaxel (18%). The final analysis included 345 events in 372 participants with a median follow-up of 33 months. Topical nitroglycerin had no demonstrable effect on PFS [median 5.0 versus 4.8 months, hazard ratio (HR) = 1.07, 95% confidence interval (CI) 0.86–1.32, P = 0.55], overall survival (median 11.0 versus 10.3 months, HR = 0.99, 95% CI 0.79–1.24, P = 0.94), or objective tumor response (31% versus 30%, relative risk = 1.03, 95% CI 0.82–1.29, P = 0.81). Headache, hypotension, syncope, diarrhea, dizziness, and anorexia were more frequent in those allocated nitroglycerin.ConclusionThe addition of topical nitroglycerin to carboplatin-based, doublet chemotherapy in NSCLC had no demonstrable benefit and should not be used or pursued further.Clinical Trials NumberAustralian New Zealand Clinical Trials Registry Number ACTRN12608000588392.     

一线序贯应用厄洛替尼与化疗治疗晚期非小细胞肺癌的临床研究

 目的　评价化疗后序贯给予厄洛替尼在一线治疗非小细胞肺癌（NSCLC）中的客观缓解率和不良反应。方法　23例PS 0～1分的ⅢB～Ⅳ期NSCLC患者一线接受GC化疗方案（吉西他滨1250 mg／m2 第1、8天,顺铂75 mg／m2 第1天或卡铂AUC＝5第1天）,并序贯给予厄洛替尼（150 mg,第15天至第28天）,每28 d为1个周期,观察患者的客观疗效及不良反应。结果　23例患者接受95个周期的化疗,所有患者均可评价疗效。完全缓解（CR）0例,部分缓解（PR）7例（30.4 %）,疾病稳定（SD）14例（60.9 %）,疾病进展（PD）2 例（8.7 %）;总体客观缓解（RR）30.4 %,疾病控制（DCR ）91.3 %。Ⅲ度以上不良反应为白细胞减少3例（13.0 %）,皮疹2例（8.7 %）,恶心呕吐、血小板减少各2例（8.7 %）,没有出现治疗相关的间质性肺病。结论　GC化疗方案序贯厄洛替尼治疗模式的近期疗效较好,不良反应在患者可耐受范围内,远期疗效有待进一步观察。     

Characteristics and outcomes of patients with advanced non-small-cell lung cancer who declined to participate in randomised clinical chemotherapy trials

There are inadequate data on the outcomes of patients who declined to participate in randomised clinical trials as compared with those of participants. We retrospectively reviewed the patient characteristics and treatment outcomes of both participants and non-participants in the two randomised trials for chemotherapy-naive advanced non-small-cell lung cancer. Trial 1 compared four platinum-based combination regimens. Trial 2 compared two sequences of carboplatin plus paclitaxel and gefitinib therapies. Nineteen of 119 (16%) and 153 (37%) patients declined to participate in Trials 1 and 2, respectively. Among the background patient characteristics, the only variable associated with trial participation or declining was the patients'' attending physicians (P<0.001). Important differences were not observed in the clinical outcomes between participants and non-participants, for whom the response rates were 30.6 vs 34.2% and the median survival times were 489 vs 461 days, respectively. The hazard ratio for overall survival, adjusted for other confounding variables, was 0.965 (95% confidence interval: 0.73–1.28). In conclusion, there was no evidence to suggest any difference in the characteristics and clinical outcomes between participants and non-participants. Trial designs and the doctor–patient relationship may have an impact on the patient accrual to randomised trials.     

Phase II study of gemcitabine plus oxaliplatin as first-line chemotherapy for advanced non-small-cell lung cancer

This phase II study evaluated the response rate and tolerability of gemcitabine-oxaliplatin chemotherapy in non-small-cell lung cancer (NSCLC) patients. Chemonaive patients with stage IIIB or IV NSCLC received gemcitabine 1000 mg m(-2) on days 1 and 8, followed by oxaliplatin 130 mg m(-2) on day 1. Cycles were repeated every 21 days for up to six cycles. From February 2002 to May 2004, 60 patients were enrolled into the study in seven Italian institutions. We observed one complete response (1.7%) and 14 partial responses (23.3%), for an overall response rate of 25.0% (95% confidence interval, 14.7-37.9%). The median duration of response was 5.9 months (range 1.5-17.1 months). With a median follow-up of 6.7 months, median time to progressive disease and overall survival were 2.7 (range 1.9-3.4 months) and 7.3 months (range 7.2-8.6 months), respectively. The main grade 3-4 haematological toxicities were transient neutropenia in 11.7% and thrombocytopenia in 8.3% of the patients. Nausea/vomiting was the main grade 3-4 nonhaematological toxicity, occurring in 10.0% of the patients. Two (3.3%) patients developed grade 3 neurotoxicity. Our results show that gemcitabine-oxaliplatin chemotherapy is active and well tolerated in patients with advanced NSCLC, deserving further study, especially for patients not eligible to receive cisplatin.     

Gemcitabine in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy: a phase II California cancer consortium trial

A phase II trial was designed to evaluate the efficacy and toxicity of gemcitabine in patients with non-small-cell lung cancer (NSCLC) previously treated with platinum-containing regimens and prospectively categorized for platinum response status. Treatment consisted of gemcitabine 1000 mg/m2 given intravenously on days 1 and 8 of a 21-day cycle. The status of p53 in pretreatment tumor tissue was assessed by immunohistochemistry (IHC). Sixty-one patients who progressed or recurred following platinum-based therapy were enrolled, 26 platinum-sensitive and 35 platinum-refractory. A median of 4 treatment courses (range, 2-7 courses) was delivered. Of the 55 patients assessable for response, there was 1 confirmed complete response and 3 with a confirmed partial response for an overall response proportion of 7%. Twenty-one patients had stable disease while 28 progressed and 2 patients had an unconfirmed partial response. Three of the responders (2 confirmed, 1 unconfirmed) were platinum-refractory. Median progression-free survival (PFS) and overall survival for all patients were 4.1 months and 8.6 months, respectively. Median PFS and overall survival for the platinum-sensitive and platinum-refractory cohorts were 5.4 months versus 3.1 months, and 11.9 months versus 7.1 months, respectively. Toxicity was principally hematologic with grade 3/4 neutropenia in 21% and grade 4 platelets in 8%. There were no treatment-related deaths. Twenty-four of 33 patients (73%) had p53-positive tumors. Although no significant association between platinum sensitivity and p53 status was seen, patients with platinum-sensitive disease and negative p53 by IHC had a trend toward longer survival compared to those with platinum-refractory disease and/or p53 positivity (P = 0.06). We concluded that salvage gemcitabine in this dose and schedule is safe and tolerable in previously platinum-treated patients with NSCLC.     

A phase II study of erlotinib in combination with bevacizumab versus chemotherapy plus bevacizumab in the first-line treatment of advanced non-squamous non-small cell lung cancer

Background

Molecularly targeted agents for non-small cell lung cancer (NSCLC) can provide similar efficacy to chemotherapy without chemotherapy-associated toxicities. Combining two agents with different modes of action could further increase the efficacy of these therapies. The TASK study evaluated the efficacy and safety of the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in combination with the anti-angiogenic agent bevacizumab as first-line therapy in unselected, advanced non-squamous NSCLC patients.

Methods

Patients were recruited from December 2007 to September 2008. Planned sample size was 200 patients, a total of 124 patients were randomized. Patients were randomized using a minimization algorithm 1:1 to receive bevacizumab (iv 15 mg/kg day 1 of each 21-day cycle) plus chemotherapy (gemcitabine/cisplatin or carboplatin/paclitaxel standard doses, 4–6 cycles) (BC arm) or bevacizumab plus erlotinib (p.o. 150 mg/day; BE arm) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). If the hazard ratio (HR) of PFS for BE relative to BC was above 1.25 at the pre-planned interim analysis in favor of BC, the study would be re-evaluated. Secondary endpoints included overall survival, response rate and safety.

Results

All randomized patients (n = 63 BE; n = 61 BC) were evaluated for the efficacy analyses. At the updated interim analysis, median PFS was 18.4 weeks (95% confidence interval [CI] 17.0–25.1) versus 25.0 weeks (95% CI 20.6–[not reached]) for BE versus BC, respectively (HR for death or disease progression, BE relative to BC, 2.05, p = 0.0183). The incidence of death was 19% for BE treatment compared with 11.5% for BC treatment. The HR for PFS at the updated interim analysis was above 1.25, therefore patients on the BE arm were permitted to change arms or switch to another drug and the study was terminated. Adverse events reported were as expected.

Conclusions

The TASK study did not show a benefit in terms of PFS for the combination of erlotinib with bevacizumab in unselected first-line advanced non-squamous NSCLC compared with chemotherapy plus bevacizumab.