EGFR mutations and clinical outcomes of chemotherapy for advanced non-small cell lung cancer: A meta-analysis

Background

This meta-analysis was performed to assess whether epidermal growth factor receptor (EGFR) mutation status was associated with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) in patients with advanced non-small cell lung cancer (NSCLC) treated with chemotherapy.

Method

We systematically identified eligible articles investigating the effects of chemotherapy in patients with NSCLC stratified by EGFR mutation status. The summary risk ratio (RR) for ORR and hazard ratios (HRs) for both PFS and OS were calculated using the inverse variance formula of meta-analysis.

Results

Identification for the current meta-analysis: 5 prospective studies (n = 875) and 18 retrospective studies (n = 1934) for ORR; 2 prospective studies (n = 434) and 10 retrospective studies (n = 947) for PFS; 2 prospective studies (n = 438) and 7 retrospective studies (n = 711) for OS. The ORR was significantly higher in patients with EGFR mutations in prospective studies (RR = 1.42; 95% confidence interval [CI], 1.16–1.74; P = 0.001), but not in retrospective studies (RR = 1.12; 95% CI, 0.96–1.32; P = 0.146). There was no obvious association between EGFR mutations and PFS both in prospective (HR = 0.84; 95% CI: 0.65–1.09; P = 0.197) and retrospective (HR = 1.02; 95% CI: 0.87–1.18; P = 0.838) studies. Association between EGFR mutations and OS was also not seen in prospective studies (HR = 0.74; 95% CI: 0.27–2.05; P = 0.566), but was seen in retrospective studies (HR = 0.48; 95% CI: 0.33–0.72; P < 0.001; I² = 75.9%; P < 0.001) with significant heterogeneity.

Conclusion

EGFR mutations in advanced NSCLC may be associated with higher ORRs to chemotherapy, but may have nothing to do with PFS and OS. Further prospective studies are required to identify the influence of EGFR mutations on chemotherapy effects in advanced 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.     

Afatinib in the treatment of EGFR mutation-positive NSCLC – A network meta-analysis

Objectives

Epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) is a specific lung cancer subtype characterized by sensitivity to treatment with EGFR tyrosine kinase inhibitors (TKIs). Two reversible EGFR TKIs (gefitinib, erlotinib) and the irreversible ErbB family blocker afatinib are currently approved for treatment of EGFR mutation-positive NSCLC, but no head-to-head trials have been reported to date. We aimed to assess the relative efficacy of the three drugs by conducting a network meta-analysis (NMA).

Materials and methods

A systematic literature review was conducted to identify all the available evidence. Outcomes of interest were progression-free survival (PFS) and overall survival. For PFS, results by investigator review were considered as not all trials assessed PFS independently. Results were analyzed using Bayesian methods.

Results

The literature search identified 246 articles that were assessed for eligibility, of which 21 studies were included in the NMA, including eight trials performed in an EGFR mutation-positive population. The estimated PFS HR (95% credible interval, CrI) for afatinib compared with gefitinib was 0.70 (0.40–1.16) and compared with erlotinib was 0.86 (0.50–1.50) in the total population. The estimated probability of being best for afatinib over all other treatments for PFS was 70% versus 27% for erlotinib and 3% for gefitinib; the estimated probability of chemotherapy being the best treatment was 0%. Estimated HR (95% CrI) in patients with common mutations was 0.73 (0.42–1.24) for afatinib compared with erlotinib and 0.60 (0.34–0.99) for afatinib compared with gefitinib. OS findings were not significantly different between treatments.

Conclusions

In the absence of direct head-to-head trial data comparing efficacy between the three EGFR TKIs, our analysis suggests that afatinib is a viable treatment alternative to erlotinib or gefitinib in terms of PFS. A direct trial-based comparison of the efficacy of these agents is warranted to clarify their relative benefits.     

Efficacy and safety of maintenance erlotinib in Asian patients with advanced non-small-cell lung cancer: a subanalysis of the phase III, randomized SATURN study

Maintenance therapy, commenced immediately after the completion of first-line chemotherapy, is a promising strategy for improving treatment outcomes in patients with non-small-cell lung cancer (NSCLC). The global phase III SequentiAl Tarceva in UnResectable NSCLC (SATURN) study evaluated the efficacy and safety of the epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor erlotinib as maintenance treatment in NSCLC patients without progression after first-line chemotherapy. We report a retrospective subanalysis of Asian patients enrolled in SATURN. Patients with advanced NSCLC with no evidence of progression after four cycles of chemotherapy were randomized to receive erlotinib 150 mg/day or placebo, until progressive disease or limiting toxicity. The co-primary endpoints of SATURN were progression-free survival (PFS) in all patients and in those with positive EGFR immunohistochemistry (IHC) status. Secondary endpoints included overall survival (OS), disease control rate, safety, quality of life (QoL) and biomarker analyses. In total, 126 patients from East and South-East Asian centers were randomized (14% of the intent-to-treat population): 88 from Korea, 28 from China and 10 from Malaysia; one patient was excluded from this analysis due to Indian ethnicity. PFS was significantly prolonged in the erlotinib treatment arm, both overall (hazard ratio [HR]: 0.57; p=0.0067) and in patients with EGFR IHC-positive disease (HR=0.50; p=0.0057). There was a trend towards an increase in OS, which reached statistical significance in the EGFR IHC-positive subgroup (p=0.0233). The overall response rate was significantly higher with erlotinib compared with placebo (24% versus 5%; p=0.0025). Erlotinib was generally well tolerated and had no negative impact on QoL in this subpopulation. The most common treatment-related adverse events were rash, diarrhea and pruritus. Erlotinib was effective and well tolerated in Asian patients, producing benefits consistent with those observed in the overall SATURN population. Maintenance treatment with erlotinib appears to be a useful option for the management of Asian patients with advanced NSCLC without progression after first-line chemotherapy.     

EGFR expression and survival in patients given cetuximab and chemoradiation for stage III non-small cell lung cancer: A secondary analysis of RTOG 0324

Purpose

We investigated whether expression of epidermal growth factor receptor (EGFR) was associated with survival and disease control in this secondary analysis of a phase II trial of cetuximab + chemoradiation for stage III non-small cell lung cancer.

Methods

Patients received cetuximab weekly before and during radiation (63 Gy/35 fractions/7 weeks) with weekly carboplatin + paclitaxel. We analyzed EGFR expression by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) in pretreatment biopsy specimens and compared findings with overall and progression-free survival (OS, PFS) and time to progression (TTP).

Results

Specimens for IHC and FISH were collected from 51 and 45 of 87 evaluable patients. Pretreatment characteristics did not differ for patients with (n = 51) or without (n = 36) EGFR IHC data, or with (n = 45) or without (n = 42) FISH data. However, patients without IHC data had worse OS (HR = 1.63, P = 0.05), worse PFS (HR = 1.88, P = 0.008), and worse TTP [HR = 1.99, P = 0.01] than those with IHC data. EGFR protein expression was not related to pretreatment characteristics or OS; FISH-positive disease was associated with better performance status but not with OS, PFS, or TTP.

Conclusions

Surprisingly, outcomes differed not by EGFR expression but by the availability of samples for analysis, underscoring the importance of obtaining biopsy samples in such trials.     

Open,randomized, multi-center phase II study comparing efficacy and tolerability of Erlotinib vs. Carboplatin/Vinorelbin in elderly patients (>70 years of age) with untreated non-small cell lung cancer

Background

Targeting the epidermal-growth-factor-receptor (EGFR) in non-small cell lung cancer (NSCLC) is an established treatment option with less toxicity compared to conventional chemotherapy. This study was undertaken to determine whether Erlotinib is non-inferior compared to chemotherapy as a first-line therapy in unselected elderly patients.

Materials and methods

Patients ≥70 years with untreated, metastatic NSCLC were randomized to Erlotinib (E), 150 mg/day or Carboplatin (AUC5) plus Vinorelbine (25 mg/m² on days 1 and 8) every three weeks (CV). Primary endpoint was progression-free survival (PFS). After progression, crossover was strongly recommended. Secondary endpoints were duration of response, 1-year survival, overall survival (OS), response rate (RR), quality of life (FACT-L), assessment of comorbidities by simplified comorbidity score (SCS) and Charlsons’ comorbidity score, safety and assessment of molecular markers.

Results

Between June 2006 and August 2008 284 pts were randomized to E (144) and CV (140). PFS was significantly inferior with E (median PFS 2.4 versus 4.6 months [HR 1.6, 75% CI 1.22–2.09, p: 0.0005]) as well as RR (7.8% v 28.3%, p: 0.0001). No significant difference in OS appeared (median E: 7.3 months versus CV: 8.4 months, HR: 1.24 [75% CI 0.9–1.71]). In never smokers PFS (median PFS: 3.7 v 4.3 m, E v CV, HR 0.72, 75% CI 0.35–1.48) and OS (median: 16.5 versus 17 months, HR 0.99 [75% CI 0.38–2.57]) were comparable. More skin toxicity and diarrhea was seen with E compared to more myelotoxicity, neurotoxicity and constipation with CV. Less severe adverse events were observed with E (81 v 102, E v CV).

Conclusion

CV had an increased efficacy compared with E in an unselected population of elderly patients with advanced NSCLC.     

Hypofractionated conformal radiotherapy for pediatric diffuse intrinsic pontine glioma (DIPG): A randomized controlled trial

Background

The pediatric diffuse intrinsic pontine glioma (DIPG) outcome remains dismal despite multiple therapeutic attempts.

Purpose

To compare the results of treatment of pediatric diffuse intrinsic pontine glioma (DIPG) using hypofractionated versus conventional radiotherapy.

Patients and methods

Seventy-one newly diagnosed DIPG children were randomized into hypofractionated (HF) (39 Gy/13 fractions in 2.6 weeks) and conventional (CF) arm (54 Gy/30 fractions in 6 weeks).

Results

The median and one-year overall survival (OS) was 7.8 months and 36.4 ± 8.2% for the hypofractionated arm, and 9.5 and 26.2 ± 7.4% for the conventional arm respectively. The 18-month OS difference was 2.2%. The OS hazard ratio (HR) was 1.14 (95% CI: 0.70–1.89) (p = 0.59).The hypofractionated arm had a median and one-year progression-free survival (PFS) of 6.6 months and 22.5 ± 7.1%, compared to 7.3 and 17.9 ± 7.1% for the conventional arm. The PFS HR was 1.10 (95% CI: 0.67–1.90) (p = 0.71). The 18-month PFS difference was 1.1%. These differences exceed the non-inferiority margin.The immediate and delayed side effects were not different in the 2 arms.

Conclusions

Hypofractionated radiotherapy offers lesser burden on the patients, their families and the treating departments, with nearly comparable results to conventional fractionation, though not fulfilling the non-inferiority assumption.     

Risk of interstitial lung disease with gefitinib and erlotinib in advanced non-small cell lung cancer: A systematic review and meta-analysis of clinical trials

Objectives

Gefitinib and erlotinib are oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) widely used in advanced non-small cell lung cancer (NSCLC). Interstitial lung disease (ILD) events have been described with these agents, although the overall risk remains unclear. We performed a systematic review and meta-analysis to determine the incidence and the relative risk (RR) associated with the use of gefitinib and erlotinib.

Materials and methods

PubMed databases were searched for articles published from January 2000 to October 2012, and abstracts presented at the American Society of Clinical Oncology and the European Society of Medical Oncology meetings held between 2000 and 2012 were searched for relevant studies. Eligible studies included randomized controlled trials with gefitinib and erlotinib in advanced NSCLC patients. Summary incidence rates, relative risks, and 95% CIs were calculated using fixed-effects or random-effects models, depending on the heterogeneity of the included studies.

Results

15,618 patients from 29 randomized controlled trials were selected for this meta-analysis. The overall incidence for all-grade ILD events was 1.2% (95% CI, 0.9–1.6%) among patients receiving gefitinib and erlotinib, with a mortality of 22.8% (95% CI, 14.6–31.0%). Compared with controls, the RR of all-grade ILD events associated with gefitinib and erlotinib was 1.53 (95% CI, 1.13–2.08; P = 0.006) using a fixed-effects model. The RR of fatal ILD events associated with EGFR TKIs treatment was 1.96 (95% CI, 1.03–3.72, P = 0.041) compared with control patients. The analysis was also stratified for drug type, study location, treatment arm, and treatment line, but no significant differences in RRs were observed.

Conclusion

Treatment with EGFR TKIs gefitinib and erlotinib is associated with a significant increase in the risk of developing both all-grade and fatal ILD events in advanced NSCLC.     

A prospective,phase II,open-label study (JO22903) of first-line erlotinib in Japanese patients with epidermal growth factor receptor (EGFR) mutation-positive advanced non-small-cell lung cancer (NSCLC)

Introduction

The epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor erlotinib is associated with survival benefits in patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC). This phase II, single-arm study examined the efficacy and safety of first-line erlotinib in Japanese patients with EGFR mutation-positive NSCLC.

Methods

Eligible patients received erlotinib 150 mg/day until disease progression or unacceptable toxicity. The primary endpoints were progression-free survival (PFS) and safety.

Results

A high degree of concordance was observed between different mutation testing methodologies, suggesting feasibility of early, rapid detection of EGFR mutations. Median PFS was 11.8 months (95% confidence interval [CI]: 9.7–15.3) at data cut-off (1 June 2012) (n = 102). Exon 19 deletions seemed to be associated with longer PFS compared with L858R mutations; T790M mutations were tentatively linked with shorter PFS. The safety profile was as expected: rash (any grade; 83%) and diarrhea (any grade; 81%) were most common. Six interstitial lung disease (ILD)-like cases were reported, and 5 were confirmed as ILD-like events by the extramural committee. Two patients died of treatment-related pneumonitis (JAPIC Clinical Trials Information number: Japic CTI-101085).

Conclusion

Erlotinib should be considered for first-line treatment in this subset of Japanese patients, with close monitoring for ILD-like events.     

Efficacy of epidermal growth factor receptor inhibitors versus chemotherapy as second-line treatment in advanced non-small-cell lung cancer with wild-type EGFR: A meta-analysis of randomized controlled clinical trials

Background

EGFR mutation status is closely related to the efficacy of EGFR-TKIs in advanced non-small cell lung cancer (NSCLC). EGFR-TKIs have become the standard first-line treatment for advanced EGFR-mutation NSCLC, while for EGFR wild-type tumors, the preferred first-line treatment is chemotherapy. However, the efficacy of EGFR-TKIs as second-line treatment in EGFR wild-type NSCLC remains controversial. We sought to evaluate the effectiveness of EGFR-TKI as second-line treatment in EGFR wild-type NSCLC.

Methods

Randomized controlled trials that compared EGFR-TKIs with chemotherapy in previously treated advanced NSCLC with wild-type EGFR were included. We performed a meta-analysis to evaluate the effectiveness of EGFR-TKIs compared with standard chemotherapy. The endpoints were progression-free survival (PFS), overall survival (OS), and objective response rate (ORR).

Results

Six randomized controlled trials with a total of 990 patients with wild-type EGFR were included: 499 in the EGFR-TKIs group and 491 in the chemotherapy group. The results indicated that in the second-line treatment of EGFR wild-type advanced NSCLC, PFS was significantly inferior in the EGFR-TKIs group versus the chemotherapy group (HR = 1.37, 95% CI = 1.20–1.56, P < 0.00001). However, this significant difference did not translate into OS (HR = 1.02, 95% CI = 0.87–1.20, P = 0.81). ORR tended to favor chemotherapy but there was no significant difference compared with EGFR-TKI (RR = 1.77, 95% CI = 0.90–3.50, P = 0.10).

Conclusions

Chemotherapy improves PFS significantly but not OS, compared with EGFR-TKIs as a second-line treatment in advanced NSCLC with wild-type EGFR. Whether EGFR-TKIs should be used in EGFR wild-type patients should be considered carefully.     

Possible differential EGFR-TKI efficacy among exon 19 deletional locations in EGFR-mutant non-small cell lung cancer

Background

Exon 19 deletion mutations (Del-19s) and the exon 21 L858R point mutation are the most common epidermal growth factor receptor (EGFR) mutations. In Del-19, several subtypes actually exist, consisting of the deletional location with or without amino acid insertion/substitution. Little evidence has been described whether the Del-19 subtype affects EGFR-tyrosine kinase inhibitor (TKI) efficacy.

Methods

Between December 2005 and July 2012, we investigated 105 patients harboring a Del-19 who had received EGFR-TKIs. Efficacies of EGFR-TKIs such as response rate (RR), progression-free survival (PFS), and overall survival (OS) were retrospectively evaluated among various patient characteristics.

Results

Among these 105 patients with Del-19s, 78 (74%) patients had a deletion from E746 (Del-E746), and 27 (26%) exhibited a deletion from L747 (Del-L747). Median PFS of Del-E746 (11.7 months, 95% confidence interval [CI]: 9.3–15.6) was significantly longer than Del-L747 (10.0 months, 95% CI: 6.4–12.7) (p = 0.022). Insertions/substitutions were found in 19 patients (18%), and 91 patients (82%) were without insertions/substitutions. Median PFS without insertions/substitutions (11.7 months, 95% CI 9.3–15.2) was significantly longer than with insertions/substitutions (10.0 months, 95% CI: 4.0–10.6) (p = 0.024). No relationships were found for RR among all patient characteristics. In multivariate analysis, performance status (PS) (0/1 vs 2/3) and initial deletion site (Del-E746 vs Del-L747) were significant factors for longer PFS, whereas PS, gender (male vs female) and histology (adeno vs squamous) for longer OS.

Conclusions

Our data indicated better efficacy of EGFR-TKI in Del-E746 than Del-L747. Deletional locations may affect EGFR-TKI efficacy.     

Safety and efficacy of addition of VEGFR and EGFR-family oral small-molecule tyrosine kinase inhibitors to cytotoxic chemotherapy in solid cancers: A systematic review and meta-analysis of randomized controlled trials

Background

The approach of combining cytotoxic chemotherapy with oral small molecule tyrosine kinase inhibitors (TKIs) has been explored in a large number of randomized trials, in a variety of tumor. We performed a systematic review and meta-analysis to evaluate the safety and efficacy of this therapeutic approach.

Patients and methods

PubMed and the ASCO databases were searched up to March 2013. We included randomized trials in which the FDA approved vascular endothelial growth factor receptor (VEGFR) or epidermal growth factor receptor-family (EGFR)-targeted TKI in combination with chemotherapy was compared with chemotherapy alone in patients with any type of solid cancer. The endpoints included safety [fatal adverse events (FAEs), treatment discontinuation, any severe (grade 3 or 4) adverse events (AEs), and individual severe AEs] and efficacy [progression-free survival (PFS), and overall survival (OS)]. The pooled relative risk (RR) or hazard ratio (HR) were calculated.

Results

A total of 16,011 patients from 43 trials were included. Compared with chemotherapy alone, the addition of a TKI significantly increased the risk of FAEs (RR, 1.63; 95% CI, 1.32–2.01), treatment discontinuation (RR, 1.80; 95% CI, 1.58–2.06), and any severe AE (RR, 1.25; 95% CI, 1.16–1.36). The addition of a TKI was associated with a significant improvement in PFS (HR, 0.82; 95% CI, 0.76–0.89), but not OS (HR, 0.99; 95% CI, 0.95–1.03).

Conclusions

It is important for physicians to weigh the risk of toxicity versus the modest PFS benefit associated with chemotherapy plus TKI in patients with solid cancers.     

Efficacy and safety of erlotinib in elderly patients in the phase IV POLARSTAR surveillance study of Japanese patients with non-small-cell lung cancer

Objective

More tolerable treatment options are needed for the large number of elderly patients with non-small-cell lung cancer (NSCLC). An analysis of the phase IV POLARSTAR surveillance study examined the safety and efficacy of erlotinib in elderly Japanese patients with previously treated NSCLC.

Materials and methods

From December 2007 to October 2009, all erlotinib-treated patients with unresectable, recurrent/advanced NSCLC in Japan were enrolled. Efficacy and safety data were stratified by age (<75 years, 75–84 years, ≥85 years). Kaplan–Meier methodology was used to estimate median progression-free survival (PFS). Safety data were collected with a focus on interstitial lung disease (ILD).

Results

A total of 9907 patients were eligible for safety assessment (<75 years, n = 7848; 75–84 years, n = 1911; ≥85 years, n = 148) and 9651 for efficacy assessment (<75 years, n = 7701; 75–84 years, n = 1815; ≥85 years, n = 135). Other baseline characteristics were balanced. The incidence of ILD (all grades) was 4.2% (<75 years), 5.1% (75–84 years), and 3.4% (≥85 years). The mortality rate due to ILD was ≤1.7% in all age groups. Other toxicities (including rash) were similar between age groups. The median PFS was 65 days (95% confidence interval [CI], 62–68) for patients aged <75 years, 74 days (95% CI, 69–82) for patients aged 75–84 years, and 72 days (95% CI, 56–93) for patients aged ≥85 years.

Conclusions

Efficacy and tolerability of erlotinib for elderly patients was not numerically inferior to that reported in younger patients. Erlotinib could be considered for elderly patients with recurrent/advanced NSCLC.     

A single-arm confirmatory study of amrubicin therapy in patients with refractory small-cell lung cancer: Japan Clinical Oncology Group Study (JCOG0901)

Objectives

We conducted an open-label, multicenter, single-arm study to confirm the efficacy and safety of amrubicin (AMR), a topoisomerase II inhibitor, for treating refractory small-cell lung cancer (SCLC).

Patients and methods

Patients with chemotherapy-refractory SCLC received 40 mg/m² AMR for 3 consecutive days, every 21 days. The primary endpoint was the overall response rate (ORR) and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety.

Results

Between November 2009 and February 2011, 82 patients were enrolled. Each patient received a median of four treatment cycles (range, 1–22 cycles). ORR was 32.9% [P < 0.0001 by the exact binomial test for the null hypothesis that ORR ≤ 10%; 95% confidence interval (CI), 22.9–44.2%]. The median PFS and OS periods were 3.5 months (95% CI, 3.0–4.3 months) and 8.9 months (95% CI, 7.6–11.3 months), respectively. Significant differences in ORR (21.4% v 45.0%; P = 0.034), PFS (median, 2.9 v 5.1 months; P = 0.0009), and OS (median, 7.9 v 13.1 months; P = 0.0128) were observed between patients previously treated with etoposide and others. Neutropenia was the most common grade 3 or 4 adverse events (93.9%), and febrile neutropenia developed in 26.8% patients. No treatment-related death occurred.

Conclusions

AMR monotherapy can be considered an effective and safe treatment option for refractory SCLC. Previous chemotherapy with etoposide may influence AMR efficacy.     

The presence of extrathoracic metastasis is more prognostic of survival than Masaoka stage (IVa/IVb) in metastatic thymic epithelial tumor: A retrospective cohort study

Purpose

Our aim in this study was to identify independent prognostic factors for overall survival (OS) in order to explain the heterogeneity of OS in patients with metastatic thymic epithelial tumor (TET).

Methods

Sixty-one consecutive patients with histologic diagnosis of Masaoka stage IV TET between January 1980 and March 2009 were analyzed at a single institution. Masaoka stage IVa was defined as pleural or pericardial dissemination, and IVb as lymphogenous or hematogenous metastasis. Metastasis outside the thoracic cage was defined as extrathoracic metastasis. To identify prognostic factors, relationships between clinicopathologic factors and outcomes were analyzed.

Results

Of the 61 patients, 30 (49.2%) had thymoma, 28 (45.9%) had thymic carcinoma, and the remaining 3 (4.9%) had an unclear histologic subtype. The Masaoka stage was IVa in 27 patients (44.3%) and IVb in 34 patients (55.7%). Significant independent adverse prognostic factors for OS were histologic subtype and extrathoracic metastasis (hazard ratio [HR] = 3.09 and 6.03, 95% CI: 1.41–6.74 and 1.89–19.30, p = 0.005 and 0.002, respectively). The presence of extrathoracic metastasis was also an independent prognostic factor for decreased progression-free survival time (PFS) (HR = 6.62, 95% CI: 1.19–24.17, p = 0.004). The only significant criterion for prognostic discrimination was the presence of extrathoracic metastasis in metastatic TET.

Conclusions

Significant independent prognostic factors for lower OS were the histologic subtype of thymic carcinoma and the presence of extrathoracic metastasis. A new concept of extrathoracic metastasis might provide additional information for the understanding of metastatic TET.     

Phase I/II trial of vorinostat (SAHA) and erlotinib for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations after erlotinib progression

Objectives

Vorinostat or suberoylanilide hydroxamic acid (SAHA) is a novel histone deacetylase inhibitor with demonstrated antiproliferative effects due to drug-induced accumulation of acetylated proteins, including the heat shock protein 90. We prospectively studied the activity of vorinostat plus erlotinib in EGFR-mutated NSCLC patients with progression to tyrosine kinase inhibitors.

Patients and methods

We conducted this prospective, non-randomized, multicenter, phase I/II trial to evaluate the maximum tolerated dose, toxicity profile and efficacy of erlotinib and vorinostat. Patients with advanced NSCLC harboring EGFR mutations and progressive disease after a minimum of 12 weeks on erlotinib were included. The maximum tolerated dose of vorinostat plus erlotinib was used as recommended dose for the phase II (RDP2) to assess the efficacy of the combination. The primary end point was progression-free-survival rate at 12 weeks (PFSR_12w). Pre-treatment plasma samples were required to assess T790M resistant mutation.

Results

A total of 33 patients were enrolled in the phase I–II trial. The maximum tolerated dose was erlotinib 150 mg p.o., QD, and 400 mg p.o., QD, on days 1–7 and 15–21 in a 28-day cycle. Among the 25 patients treated at the RDP2, the most common toxicities included anemia, fatigue and diarrhea. No responses were observed. PFSR_12w was 28% (IC95%: 18.0–37.2); median progression-free survival (PFS) was 8 weeks (IC 95%: 7.43–8.45) and overall survival (OS) 10.3 months (95% CI: 2.4–18.1).

Conclusion

Full dose of continuous erlotinib with vorinostat 400 mg p.o., QD on alternative weeks can be safely administered. Still, the combination has no meaningful activity in EGFR-mutated NSCLC patients after TKI progression.     

Treatment patterns and outcomes in patients with non-squamous advanced non-small cell lung cancer receiving second-line treatment in a community-based oncology network

Objectives

This retrospective study used the US Oncology iKnowMed™ database, billing claims, and chart reviews to report treatment patterns and outcomes in late-stage non-small cell lung cancer (NSCLC) in US community oncology practices.

Materials and methods

Eligibility criteria included non-squamous NSCLC, stage IIIB/IV at diagnosis, ECOG performance status (PS) <3, and initiation of 2nd-line therapy (defined as index date) between 1/1/2007 and 6/30/2011 with ≥1 year follow-up. Key outcomes were overall survival (OS), progression-free survival (PFS), time-to-progression (TTP), and time-to-hospitalization (post-index date). Kaplan–Meier and Cox proportional hazard models were used to characterize the distribution and predictors of outcomes.

Results

1168 patients were eligible for the study. The most frequent 2nd-line therapies were pemetrexed (54.4%), erlotinib-containing regimens (17.6%), and docetaxel (10.0%). Median OS and PFS were 7.5 (95% confidence interval [CI]: 6.6–8.4) and 4.1 (95% CI: 3.7–4.5) months, respectively; 57% of patients were hospitalized post-index date. EGFR testing rates were 2.3% before 2010, 15.2% in 2010, and 32.0% in 2011 (P < .001). Of EGFR-positive patients, 50.0% received erlotinib-containing regimens compared with 16.9% of EGFR-negative patients (P = 0.001). An increased risk of shorter time-to-hospitalization, after controlling for other covariates, was associated with PS = 1 (hazard ratio [HR] = 1.51; P < .001) or PS = 2 (HR = 1.68; P = .001) compared with PS = 0, pre-existing comorbid fatigue (HR = 1.64; P = .003) compared with no comorbid fatigue, and progression (HR = 1.92; P < .001), when it occurred, compared with no progression. Compared with other 2nd-line treatment, erlotinib-containing regimens prolonged adjusted TTP (HR = 0.69; P = .015).

Conclusions

This retrospective observational study provides new insights into treatment patterns, biomarker testing, and outcomes in advanced NSCLC within the context of a large community oncology network. Outcomes of these community practice patients, although poor, were similar to those reported in 2nd-line clinical trials for relevant regimens. EGFR testing in community practice rose rapidly after 2010.     

A multicenter phase II study of sorafenib monotherapy in clinically selected patients with advanced lung adenocarcinoma after failure of EGFR-TKI therapy (Chinese Thoracic Oncology Group,CTONG 0805)

Objectives

Aim of the study was to investigate efficacy and safety of sorafenib in patients with advanced lung adenocarcinoma after failure of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) therapy.

Patients and methods

Patients who were diagnosed with stage IIIB or stage IV lung adenocarcinoma, and benefited from one prior EGFR-TKI therapy and then failed, were eligible. No more than one previous chemotherapy regimen was permitted. Patients received oral sorafenib 400 mg twice daily continuously until disease progression or intolerable toxicity. Primary endpoint was disease control rate (DCR). Secondary endpoints included safety, progression-free survival (PFS) and overall survival (OS). For patients who agreed to provide peripheral blood or tumor tissue, we analyzed the genotype of Bcl-2-interacting mediator of cell death (BIM) deletion polymorphism and EGFR mutation status.

Results

Of 65 enrolled patients, 64 were evaluable. The DCR was 32.8%, which did not meet the predefined statistical hypothesis of 38.4%. The median PFS and OS were 3.7 months [95% (confidence interval), 3.5–3.9 months] and 7.4 months (95% CI, 5.7–9.2 months), respectively. Logistic regression analysis showed no correlation between DCR and age, gender, smoking status and performance status. Hand-foot syndrome (HFS) was the predominant toxicity occurring in 71.9% of patients. Fourteen patients (21.9%) had ≥grade 2 dermatologic reactions that resulted sorafenib dose reduction in three patients (4.7%). Of 36 patients, the BIM deletion polymorphism was found in 3, and no response to sorafenib was observed. In 30 tumor tissues, 22 EGFR active mutations were found. The DCR had no significant difference between mutation-positive and wild-type patients (31.8% vs. 42.9%, respectively; HR, 0.622; p = 0.665).

Conclusion

Sorafenib monotherapy did not achieve positive result in patients defined in our trial and we need better biomarker to determine the population who can benefit from sorafenib treatment (ClinicalTrials.gov number: NCT00922584).     

Approval summary: erlotinib maintenance therapy of advanced/metastatic non-small cell lung cancer (NSCLC)

On April 16, 2010, the U. S. Food and Drug Administration (FDA) approved erlotinib tablets (Tarceva®; OSI Pharmaceuticals, Inc., Melville, NY) for maintenance treatment of patients with stage IIIB/IV non-small cell lung cancer (NSCLC) whose disease had not progressed after four cycles of platinum-based first-line chemotherapy.In total, 889 patients received either erlotinib (150 mg) or placebo once daily. Progression-free survival (PFS), in all patients and in patients with epidermal growth factor receptor (EGFR)⁺ tumors by immunohistochemistry (IHC), was the primary efficacy endpoint. Overall survival (OS) was a secondary sponsor endpoint but was the primary regulatory endpoint.Median PFS times were 2.8 months and 2.6 months in the erlotinib and placebo arms, respectively (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.62–0.82; p < .001). Median OS times were 12.0 months and 11.0 months, favoring erlotinib (HR, 0.81; 95% CI, 0.70–0.95). The PFS and OS HRs in patients with EGFR⁺ tumors by IHC were 0.69 (95% CI, 0.58–0.82) and 0.77 (95% CI, 0.64–0.93), respectively. The PFS and OS HRs in patients with EGFR⁻ tumors by IHC were 0.77 (95% CI, 0.51–1.14) and 0.91 (95% CI, 0.59–1.38), respectively.Following disease progression, 57% of placebo-treated patients received additional chemotherapy, compared with 47% of erlotinib-treated patients. Fourteen percent of placebo-treated patients received erlotinib or gefitinib, 31% received docetaxel, and 14% received pemetrexed. In total, 59% of placebo-treated patients who received treatment received FDA approved second-line NSCLC drugs.The most common adverse reactions in patients receiving erlotinib were rash and diarrhea.     

Reduced chemotherapy sensitivity in EGFR-mutant lung cancer patient with frontline EGFR tyrosine kinase inhibitor

Objectives

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a standard first-line treatment for EGFR-mutant patients with non-small cell lung cancer (NSCLC). However, it remains unclear whether frontline EGFR TKIs affect subsequent chemo-sensitivity in EGFR-mutant patients. This study compared chemo-sensitivity in patients treated with post-TKI chemotherapy and first-line chemotherapy controls.

Materials and methods

This study included 203 EGFR-mutant patients. The study group contained 68 patients treated with chemotherapy after first-line EGFR-TKI and the control group contained 135 patients who received first-line chemotherapy. The response rate (RR), progression-free survival (PFS) and overall survival (OS) were assessed.

Results

In study group, the RR of chemotherapy was 13.2% compared with 34.1% in the control group (P = 0.002). The median PFS of chemotherapy in the control group was significantly longer than in the study group (6.9 vs. 3.9 months, P < 0.001), while the RR (76.5% vs. 68.9%, P = 0.259) and PFS (11.0 vs. 10.2 months) of EGFR-TKI were similar between first- and second-line treatment. Cox regression analyses indicated that prior EGFR-TKI treatment had a higher risk for disease progression during chemotherapy treatment [hazard ratio (HR) = 3.06; 95% CI = 2.12–4.42, P < 0.001]. Median overall survival was 31.7 months in the control group and 23.5 months in the study group (P < 0.001). The adjusted HR for death in the study group was 1.91 (95% CI = 1.33–2.76; P < 0.001).

Conclusion

In EGFR-mutant patients, frontline EGFR-TKI significantly reduced the sensitivity of subsequent chemotherapy compared with that of TKI-naïve frontline chemotherapy. These findings need to be validated in further randomized trials.