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.     

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.     

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.     

Evaluation of EGFR protein expression by immunohistochemistry using H-score and the magnification rule: Re-analysis of the SATURN study

Introduction

The phase III SATURN study demonstrated that first-line maintenance erlotinib extended progression-free survival (PFS) and overall survival (OS) versus placebo in patients with advanced non-small cell lung cancer (NSCLC). Analysis of epidermal growth factor receptor (EGFR) expression by immunohistochemistry (IHC) found no significant interaction between EGFR IHC status and PFS (p = 0.63) or OS (p = 0.52). The FLEX study of first-line cetuximab plus chemotherapy demonstrated that EGFR IHC expression was predictive of improved OS with cetuximab when assessed by H-score with a magnification rule. This novel method was used to reassess samples from SATURN.

Methods

The H-score method assigned a score of 0–300 to each patient, based on the percentage of cells stained at different intensities viewed at various magnifications. The discriminatory threshold was set at 200, per the FLEX study, and existing samples were re-read and classed as low (H-score < 200) or high (≥200) EGFR expression. PFS and OS were re-analyzed based on these new classifications.

Results

In the overall and EGFR wild-type populations, erlotinib provided a consistent survival benefit versus placebo. Hazard ratios (HRs) in the overall population were similar between EGFR IHC-positive and -negative patients for median PFS (HR 0.68 [95% confidence interval (CI) 0.53–0.86] and 0.76 [95% CI 0.62–0.93], respectively) and OS (HR 0.80 [95% CI 0.62–1.05] and 0.80 [95% CI 0.64–1.01] for IHC-positive and IHC-negative, respectively). In the EGFR wild-type population, HRs were again similar between EGFR IHC-positive and -negative subpopulations for PFS (HR 0.69 [95% CI 0.51–0.95] and 0.84 [95% CI 0.63–1.12], respectively) and OS (HR 0.78 [95% CI 0.55–1.10] and 0.76 [95% CI 0.55–1.05], respectively).

Conclusions

These data suggest that EGFR IHC does not have value as a marker to predict erlotinib benefit in the first-line maintenance setting for 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.     

Evidence supporting contemporary post-operative radiation therapy (PORT) using linear accelerators in N2 lung cancer

Purpose

Post-operative radiotherapy (PORT) treatment for lung cancer declined since a meta-analysis failed to show benefit in patients with N2 disease. Because several included studies employed outmoded radiation planning and delivery techniques, we sought to determine whether PORT with modern technology benefits patients with N2 disease.

Methods

We conducted searches of the published literature. For inclusion, studies must have included patients with stage III-N2 lung cancer treated with PORT using only linear accelerators, used a control group that did not receive PORT, and reported outcome data for overall survival (OS). Prospective and retrospective analyses were included. Exclusion criteria were the use of cobalt devices or orthovoltage radiation.

Results

Data were evaluated with random-effects models. Three prospective and eight retrospective studies were included. The PORT and no-PORT groups included 1368 and 1360 patients, respectively. The PORT group had significantly improved OS over the no-PORT group (hazard ratio [HR] = 0.77, 95% confidence interval [CI] 0.62–0.96, P = 0.020). Locoregional recurrence-free survival (LRFS) in 10 studies for which data was available was also improved in the PORT group (HR = 0.51, CI 0.41–0.65, P < 0.001).

Conclusions

PORT was associated with significantly lower risk of death and locoregional recurrence in patients with N2 lung cancer. Our study was limited by lack of access to individual patient data, which would have enabled more detailed analyses. Regardless, data thus far suggest PORT may be associated with a survival benefit. Given a lack of large-scale prospective data, clinical trials evaluating PORT with modern technology are warranted.     

Efficacy and safety of maintenance pemetrexed in patients with advanced nonsquamous non-small cell lung cancer following pemetrexed plus cisplatin induction treatment: A cross-trial comparison of two phase III trials

Objectives

Two phase III trials of advanced NSCLC patients were compared to examine relative efficacy and safety of differing treatment regimens. The JMDB trial investigated first-line pemetrexed–cisplatin (pemetrexed 500 mg/m² plus cisplatin 75 mg/m² every 21 days; maximum: 6 cycles). The PARAMOUNT phase III trial compared maintenance pemetrexed versus placebo after patients with nonsquamous NSCLC completed 4 cycles of first-line pemetrexed–cisplatin without disease progression.

Methods

Overall survival (OS) and progression-free survival (PFS), analyzed by Kaplan–Meier and Cox methods, and toxicity rates were compared between the PARAMOUNT arms and a selected homogeneous population from JMDB: 346 patients with disease and prior treatment characteristics matching the PARAMOUNT population.

Results

Outcomes for the PARAMOUNT placebo arm were similar to the JMDB homogeneous group (median PFS: 5.6 versus 6.2 months, p = 0.117, HR = 1.16; median OS: 14.0 versus 14.2 months, p = 0.979, HR = 1.00). The PARAMOUNT maintenance pemetrexed group had statistically superior efficacy compared with the JMDB homogeneous group (median PFS: 7.5 versus 6.2 months, p < 0.00001, HR = 0.66; median OS: 16.9 versus 14.2 months, p = 0.003, HR = 0.75). Patients who received pemetrexed maintenance (median 4 cycles, range 1–44) following 4 cycles of pemetrexed–cisplatin exhibited a higher incidence of drug-related serious adverse events compared with JMDB patients (median 6 cycles of pemetrexed–cisplatin) (10.6% versus 2.9%); grade 3/4 fatigue and renal toxicity were also higher in the pemetrexed arm of PARAMOUNT.

Conclusions

The across-trial comparison of a relevant JMDB study population with the two arms of the PARAMOUNT study supported the efficacy of the pemetrexed continuation maintenance strategy and suggested the results are not influenced by limiting the pemetrexed–cisplatin induction treatment to four cycles. Although longer exposure to pemetrexed–cisplatin or maintenance pemetrexed increased some toxicities, the overall incidence remained low, underscoring the relative safety of these treatment regimens.     

Temporal trends from 1986 to 2008 in overall survival of small cell lung cancer patients

Objectives

An assessment of temporal trends in patient survival is important to determine the progress toward patient outcomes and to reveal where advancements must be made. This study assessed temporal changes spanning 22 years in demographics, clinical characteristics, and overall survival of small cell lung cancer (SCLC) patients.

Materials and methods

This analysis included 1032 SCLC patients spanning two time-periods from the H. Lee Moffitt Cancer Center and Research Institute: 1986–1999 (N = 410) and 2000–2008 (N = 622). Kaplan–Meier survival curves and log-rank statistics were used to assess survival rates across the two time-periods and multivariable Cox proportional hazards models were used to generate hazard ratios (HRs) and 95% confidence intervals (CIs).

Results

The overall 5-year survival rate significantly increased from 8.3% for the 1986–1999 time-period to 11.0% (P < 0.001) for the 2000–2008 time-period, and the median survival time increased from 11.3 months (95% CI 10.5–12.7) to 15.2 months (95% CI 13.6–16.6). We also observed significant increases in stage-specific median survival times and survival rates across the two time-periods. A multivariable Cox proportional hazards model for the entire cohort revealed significant increased risk of death for patients diagnosed in 1986–1999 (HR = 1.29; 95% CI 1.11–1.49), patients diagnosed between 60 and 69 years of age (HR = 1.33; 95% CI 1.04–1.49) and over 70 years of age (HR = 1.63; 95% CI 1.26–2.11), men (HR = 1.33; 95% CI 1.16–1.53), patients with no first course treatment (HR = 2.17; 95% CI 1.57–3.00) and extensive stage SCLC (HR = 2.79; 95% CI 2.35–3.30).

Conclusion

This analysis demonstrated significant improvements in overall and stage-specific median survival times and survival rates of SCLC patients treated at the Moffitt Cancer Center from 1986 to 2008.     

Prevalence and effectiveness of first-, second-, and third-line systemic therapy in a cohort of unselected patients with advanced non-small cell lung cancer

Systemic therapy is the most relevant option for patients with advanced non-small-cell lung cancer (NSCLC) and many receive therapies beyond first-line. Little is known on response, progression free survival (PFS) and overall survival (OS) and their prognostic factors after second- and third-line therapy in daily clinical practice. Between January 2003 and July 2007, 406 consecutive patients were included in this prospective observational study and followed up until August 2010. At each treatment line the timing and kind of therapy, best response achieved, sites and time of progression were documented. Multiple logistic and Cox-regression models were used to analyse prognostic factors for achieving disease control (DC: response or disease stabilization), PFS and OS after different therapy lines. DC rate and median PFS decreased from 64% and 146 days, to 41% and 49 days, and to 39% and 51 days in response to first-, second- and third-line, respectively. A strong predictor for a worse outcome after second-line was development of new metastases after first-line therapy (DC: OR = 2.50; 95% CI: 1.30-4.83; p-value = 0.006; PFS: HR = 1.53; 95% CI: 1.13-2.06; p-value = 0.005) or achieving no DC after first-line (OS: HR = 1.41; 95% CI: 1.01-1.97; p-value = 0.041). Achieving no DC after second-line was a strong negative predictor for all outcome measures after third-line therapy (DC: OR = 5.10; 95% CI: 1.56-16.6; p-value = 0.007; PFS: HR = 2.00; 95% CI: 1.23-3.27; p-value = 0.005; OS: HR = 1.69; 95% CI: 1.02-2.79; p-value = 0.042). In conclusion, response in previous line and no involvement of new metastases after progression were relevant positive prognostic factors. However, further research is necessary to identify optimal therapy sequences.     

Efficacy and safety of pemetrexed/cisplatin versus gemcitabine/cisplatin as first-line treatment in Chinese patients with advanced nonsquamous non-small cell lung cancer

Objectives

Retrospective subgroup analysis in JMDB study indicates that the between-arm differences in overall survival (OS) in the East Asian subgroup were consistent with those observed in the entire JMDB study population. This bridging study (JMIL) further evaluated the efficacy and safety of first-line pemetrexed/cisplatin (PC) versus gemcitabine/cisplatin (GC) in Chinese patients with nonsquamous non-small cell lung cancer (NSCLC). The primary endpoint of this local registration trial was designed to compare OS in the combined dataset, consisting of Chinese patients in JMIL and 1252 nonsquamous patients in JMDB.

Materials and methods

Chinese patients with stage IIIB/IV nonsquamous NSCLC were randomly assigned (1:1) to 6 cycles maximum (21 days/cycle) of pemetrexed 500 mg/m² + cisplatin 75 mg/m² (day 1), or gemcitabine 1250 mg/m² (days 1 and 8) + cisplatin 75 mg/m² (day 1).

Results

In JMIL, 256 Chinese patients were randomized (PC, n = 126; GC, n = 130). Patient baseline characteristics were balanced between treatment arms. In the combined dataset, PC was superior to GC in prolonging OS, with adjusted hazard ratio (HR) of 0.87 (95% CI: 0.77–0.98, p = 0.023) and median OS of 11.76 versus 10.94 months. In the JMIL-only population, no significant OS difference observed between treatment arms (adjusted HR = 1.03 [95% CI: 0.77–1.39, p = 0.822]; unadjusted HR = 0.996 [95% CI: 0.74–1.33, p = 0.980]), nor for other secondary efficacy endpoints. Significantly fewer patients in the PC arm experienced drug-related grade 3/4 toxicities, 54 (43.2%) versus 71 (55.9%) for GC (p = 0.045), with significantly lower rates of leukocytopenia, thrombocytopenia, and fatigue.

Conclusion

This study showed that in the combined population, OS of PC was superior to GC, while in the Chinese-only population, no significant difference was observed; a better safety and risk/benefit profile was found in the PC arm. A PC regimen should be considered as a standard of care in Chinese nonsquamous NSCLC patients in a first-line setting.     

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.     

A randomized,double-blind,placebo-controlled phase 2 study of tigatuzumab (CS-1008) in combination with carboplatin/paclitaxel in patients with chemotherapy-naïve metastatic/unresectable non-small cell lung cancer

Introduction

Tigatuzumab, a humanized monoclonal DR5 agonist antibody induces apoptosis in human cancer cell lines. The objective of this study was to investigate the antitumor effects of tigatuzumab combined with carboplatin/paclitaxel in chemotherapy-naïve patients with metastatic/unresectable non-small cell lung cancer (NSCLC).

Methods

Patients with histologically or cytologically confirmed NSCLC stage IIIB/IV disease by RECIST (version 1.0) and ECOG-PS 0–1 were enrolled at 15 European sites. Patients received tigatuzumab or placebo intravenously with carboplatin/paclitaxel every 3 weeks (1 cycle) for up to 6 cycles. The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), objective response rate and safety.

Results

97 patients were analyzed for efficacy (49 tigatuzumab; 48 placebo). Median PFS (95% CI) was 5.4 months (3.3, 6.6) for tigatuzumab compared with 4.3 months (4.1, 5.8) for placebo. Median OS (95% CI) was 8.4 months (6.9, 16.3) for tigatuzumab versus 9.0 months (7.6, 14.5) for placebo. 12 patients (24.5%) in the tigatuzumab arm and 11 patients (22.9%) in the placebo arm had partial response. No patient had complete response. In a prospectively-defined Fc gamma receptor genotype subset (n = 25), there was a non-significant trend toward increased PFS with tigatuzumab versus placebo (HR = 0.47; 95% CI: 0.16, 1.35) but no difference in OS. Tigatuzumab was well tolerated. However, grade 3/4 neutropenia was reported in 10 patients (20.4%) receiving tigatuzumab compared with 4 patients (8.3%) receiving placebo.

Conclusions

Tigatuzumab was well tolerated but did not improve efficacy of carboplatin/paclitaxel in systemic therapy-naïve, unselected advanced NSCLC patients. Clinical trials identifier: NCT00991796.     

Cross-validation analysis of the prognostic significance of mucin expression in patients with resected non-small cell lung cancer treated with adjuvant chemotherapy: Results from IALT,JBR.10 and ANITA

Introduction

CALGB 9633 was a randomized trial of observation versus adjuvant chemotherapy for patients with stage IB non-small cell lung cancer (NSCLC). In CALGB 9633, the presence of mucin in the primary tumor was associated with shorter disease-free survival (DFS; hazard ratio (HR) = 1.9, p = 0.002) and overall survival (OS; HR = 1.9, p = 0.004).

Methods

To validate these results, mucin staining was performed on primary tumor specimens from 780 patients treated on IALT, 351 on JBR.10 and 150 on ANITA. The histochemical technique using mucicarmine was performed. The prognostic value of mucin for DFS and OS was tested in a Cox model stratified by trial and adjusted for clinical and pathological factors. A pooled analysis of all 4 trials was performed for the predictive value of mucin for benefit from adjuvant chemotherapy.

Results

The cross-validation group had 48% squamous, 37% adenocarcinoma and 15% other NSCLC compared with 29%, 56%, and 15%, respectively in CALGB. Among 1262 patients with assessable results, mucin was positive in IALT 24%, JBR.10 30%, ANITA 22% compared with 45% in CALGB. Histology was the only significant covariate (p < 0.0001) in multivariate analysis with mucin seen more commonly in adenocarcinoma (56%) compared with squamous (5%) and other NSCLC (15%). Mucin was a borderline negative prognostic factor for DFS (HR = 1.2 [1.0–1.5], p = 0.06) but not significantly so for OS (HR = 1.1 [0.9–1.4], p = 0.25). Prognostic value did not vary according to histology: HR = 1.3 [1.0–1.6] in adenocarcinoma vs. 1.6 [1.2–2.2] for DFS in other histology (interaction p = 0.69). Mucin status was not predictive for benefit from adjuvant chemotherapy (test of interaction: DFS p = 0.27; OS p = 0.49).

Conclusions

Mucin was less frequent in the cross-validation group due to its higher percentage of squamous cell carcinomas. The negative impact of mucin was confirmed for DFS but not for OS. Mucin expression was not predictive of overall survival benefit from adjuvant chemotherapy.     

Radical treatment of synchronous oligometastatic non-small cell lung carcinoma (NSCLC): Patient outcomes and prognostic factors

Objectives

Metastatic non-small cell lung carcinoma (NSCLC) generally carries a poor prognosis, and systemic therapy is the mainstay of treatment. However, extended survival has been reported in patients presenting with a limited number of metastases, termed oligometastatic disease. We retrospectively reviewed the outcomes of such patients treated at two centers.

Materials and methods

From September 1999–July 2012, a total of 61 patients with 1–3 synchronous metastases, who were treated with radical intent to all sites of disease, were identified from records of two cancer centers. Treatment was considered radical if it involved surgical resection and/or delivery of radiation doses ≥13 × 3 Gy.

Results

Besides the primary tumor, 50 patients had a solitary metastasis, 9 had two metastases, and 2 had three metastases. Locations of metastases included the brain (n = 36), bone (n = 11), adrenal (n = 4), contralateral lung (n = 4), extra-thoracic lymph nodes (n = 4), skin (n = 2) and colon (n = 1). Only one patient had metastases in two different organs. Median follow-up was 26.1 months (m), median overall survival (OS) was 13.5 m, median progression free survival (PFS) was 6.6 m and median survival after first progression (SAFP) was 8.3 m. The 1- and 2-year OS were, 54% and 38%, respectively. Significant predictors of improved OS were: smaller radiotherapy planning target volume (PTV) (p = 0.004) and surgery for the primary lung tumor (p < 0.001). Factors associated with improved SAFP included surgery for the primary lung tumor, presence of brain metastases, and absence of bone metastases. No significant differences in outcomes were observed between the two centers.

Conclusion

Radical treatment of selected NSCLC patients presenting with 1–3 synchronous metastases can result in favorable 2-year survivals. Favorable outcomes were associated with intra-thoracic disease status: patients with small radiotherapy treatment volumes or resected disease had the best OS. Future prospective clinical trials, ideally randomized, should evaluate radical treatment strategies in such patients.     

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.     

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 multicenter phase II study to evaluate the efficacy and safety of gefitinib as first-line treatment for Korean patients with advanced pulmonary adenocarcinoma harboring EGFR mutations

This study was designed to prospectively evaluate the efficacy and safety of first-line gefitinib treatment in patients with advanced pulmonary adenocarcinoma harboring epidermal growth factor receptor (EGFR) mutations and to explore the molecular factors affecting the efficacy of gefitinib. Tumor tissue, derived from either the original tumor or the metastatic or recurrent site was taken from chemo-naïve pts with advanced (stage IIIB, IV, and recurrent) pulmonary adenocarcinoma. Tumor genomic DNA underwent direct sequencing for EGFR exons 18, 19, 20, and 21. Patients with EGFR mutations received 250 mg of gefitinib daily until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression free survival (PFS), overall survival (OS) and tolerability. Out of 147 screened patients, 45 pts (31%) had EGFR mutations and received gefitinib. The most common EGFR mutations were in-frame exon 19 deletions (29 pts, 64%) and L858R point mutation in exon 21 (15 pts, 33%). One patient had atypical mutation of L861Q in exon 21. The ORR was 53.3% (95% CI, 38.6-67.9) and disease control rate (DCR) including stable disease was 86.7%. The median progression free survival (PFS) was 398 days and the median overall survival (OS) was 819 days. Treatment was well tolerated. Grade 3/4 adverse events (AEs) were reported by 6 patients and treatment-related Grade 3 AEs by 3 patients. There were no treatment-related Grade 4 AEs. Exploratory subgroup analysis according to the EGFR mutation subtypes was carried out. The ORR and DCR were higher in patients with exon 19 deletions than those with L858R (62.1% vs 33.3%; P = 0.0705 and 96.6% vs 66.7%; P = 0.0062, respectively). All 4 patients with progressive disease had a L858R mutation. No secondary resistant mutations such as T790M mutation or insertions in exon 20 were found in those patients. In addition, OS was significantly better in patients with exon 19 deletions than those with L858R (24-month OS rate was 72.1% vs 32.0%, P = 0.0148). Gefitinib as the first-line treatment for Korean patients with advanced pulmonary adenocarcinoma harboring EGFR mutations was effective and well tolerated. Subgroup analysis suggests that the benefit from gefitinib treatment was more prominent in patients with the exon 19 deletion mutations (ClinicalTrials.gov number, NCT00344773).     

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.     

Blood vessel invasion is a major feature and a factor of poor prognosis in sarcomatoid carcinoma of the lung

Objectives

Pulmonary sarcomatoid carcinomas (SC) are highly disseminated types of non-small-cell lung carcinoma. Their prognosis is poor. New therapeutic targets are needed to improve disease management.

Materials and methods

From 1995 to 2013, clinical and survival data from all consecutive patients with surgically treated SC were collected. Pathological and biomarker analyses were performed: TTF1, P63, c-MET and ALK expression (immunohistochemistry), PAS staining, ALK rearrangement (FISH), and EGFR, KRAS, HER2, BRAF, PIK3CA, and MET genes mutations (PCR).

Results

Seventy-seven patients were included. Median age was 61 years (53–69). Histological subtypes were pleomorphic carcinoma (78%), carcinosarcoma (12%), and giant-cell and/or spindle-cell carcinoma (10%). Blood vessel invasion (BVI) was present in 90% of cases. Morphology and immunohistochemistry were indicative of an adenocarcinoma, squamous, and adenosquamous origin in 41.5%, 17% and 11.5%, respectively, 30% remained not-otherwise-specified. KRAS, PIK3CA, EGFR, and MET mutations were found in 31%, 8%, 3%, and 3%, respectively. No tumors had HER2 or BRAF mutations, or ALK rearrangement, whereas 34% had a c-MET positive score. Five-year overall survival (OS) was 29% for the whole population. At multivariate analysis, tumor size <50 mm (HR = 1.96 [1.04–3.73], p = 0.011), no lymph-node metastasis (HR = 3.25 [1.68–6.31], p < 0.0001), no parietal pleural invasion (HR = 1.16 [1.06–1.28], p = 0.002), no BVI (HR = 1.22 [1.06–1.40], p = 0.005), and no squamous component (HR = 3.17 [1.48–6.79], p = 0.01) were associated with longer OS. Biomarkers did not influence OS.

Conclusion

Dedifferentiation in NSCLC could lead to SC and an epithelial subtype component could influence outcome. BVI was present in almost all SCs and was an independent factor of poor prognosis.