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).     

Current views on the role of Notch signaling and the pathogenesis of human leukemia

Background

Gefitinib was the first epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) approved for the treatment of advanced non-small cell lung cancer (NSCLC). Few treatment options are available for NSCLC patients who have responded to gefitinib treatment and demonstrated tumor progression. The present study was conducted to evaluate the efficacy and toxicity of the 2^nd EGFR-TKI administration.

Methods

We retrospectively analyzed 11 patients who had obtained a partial response (PR) or stable disease (SD) with gefitinib treatment and were re-treated with EGFR-TKI after failure of the initial gefitinib treatment.

Results

Three patients (27%) were treated with gefitinib as the 2^nd EGFR-TKI, and 8 patients (73%) received erlotinib. Only one patient (9%) showed PR, 7 (64%) achieved SD, and 3 (27%) had progressive disease. The disease control rate was 73% (95% CI, 43% - 91%) and the median progression-free survival was 3.4 months (95% CI, 2 - 5.2). The median overall survival from the beginning of the 2^nd EGFR-TKI and from diagnosis were 7.3 months (95% CI, 2.7 - 13) and 36.7 months (95% CI, 23.6 - 43.9), respectively. No statistical differences in PFS or OS were observed between gefitinib and erlotinib as the 2^nd EGFR-TKI (PFS, P = 0.23 and OS, P = 0.052). The toxicities associated with the 2^nd EGFR-TKI were generally acceptable and comparable to those observed for the initial gefitinib therapy.

Conclusions

Our results indicate that a 2^nd EGFR-TKI treatment can be an effective treatment option for gefitinib responders.     

T790M mutation is associated with better efficacy of treatment beyond progression with EGFR-TKI in advanced NSCLC patients

Background and purpose

Continuous EGFR-TKI treatment beyond progression has shown promising benefit for some patients with acquired resistance to EGFR-TKIs. The aim of this study was to investigate the association of secondary T790M mutation at the time of progression with the efficacy of EGFR-TKI treatment beyond progression.

Methods

From March 2011 to March 2013, patients with advanced NSCLC who developed acquired resistance to EGFR-TKI and where a re-biopsy was performed at Tongji University Cancer Institute were included into this study. Scorpion ARMS was used to detect EGFR mutation status.

Results

A total of 54 patients were enrolled in this study with a median progression-free survival time (PFS1) of 10.9 months according to RECIST criteria. In all, 53.7% (29/54) had T790M mutation after the failure of EGFR-TKIs; PFS1 was not statistically significantly different between patients with T790M mutation and without (13.0 vs. 10.5 months, p = 0.894). In all, 41 patients received TKI treatment beyond progression, including 22 with local progression to receive additional local therapy and 19 with gradual progression to receive additional chemotherapy. The median progression-free survival time (PFS2) of patients who received EGFR-TKI beyond progression treatment was 3.5 months (95% CI, 2.689–4.311). Patients with T790M mutation had significantly longer PFS2 (6.3 vs. 2.6 months, p = 0.002) and overall survival (39.8 vs. 23.2 months, p = 0.044) than those without.

Conclusion

Patients with secondary T790M mutation at the time of progression having gradual or local progression after acquired resistance to EGFR-TKI benefit more from EGFR-TKI treatment beyond progression compared to those without T790M mutation.     

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.     

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.     

Erlotinib after gefitinib failure in relapsed non-small cell lung cancer: clinical benefit with optimal patient selection

Background

Recent reports have suggested that erlotinib therapy after gefitinib failure requires optimal patient selection to obtain clinical benefits in relapsed non-small cell lung cancer (NSCLC). However, insufficient evidence exists to determine which clinical factors best identify patients who benefit from erlotinib therapy.

Methods

One hundred twenty-five patients with relapsed NSCLC who had received erlotinib therapy after gefitinib failure were retrospectively evaluated between January 2008 and May 2009.

Results

The response rate (RR), disease control rate (DCR), and median progression-free survival (PFS) for all patients were 9% (95% confidence interval [CI], 5-15%), 44% (95% CI, 35-53%), and 2.0 months (95% CI, 1.4-2.5 months), respectively. The median survival time was estimated to be 11.8 months (95% CI, 6.4-16.0 months). Using multivariate analysis, good performance status (PS), EGFR mutation-positive status, and benefit from prior gefitinib therapy were identified as significant predictive factors for disease control. Using a proportional hazards model, benefit from prior gefitinib therapy, good PS, and insertion of cytotoxic chemotherapies between gefitinib and erlotinib therapies emerged as significant predictive factors for longer PFS. Thirty-two patients with concomitant PS 0/1, benefit from prior gefitinib therapy, and insertion of cytotoxic chemotherapies between gefitinib and erlotinib therapies benefitted more from erlotinib therapy: RR, 25% (95% CI, 12-43%); DCR, 72% (95% CI, 53-86%); and median PFS, 3.4 months (95% CI, 2.4-4.9 months).

Conclusions

Higher efficacy of erlotinib after gefitinib failure can be achieved with proper patient selection criteria, including good PS, benefit from prior gefitinib therapy, and insertion of cytotoxic chemotherapies between gefitinib and erlotinib therapies.     

An evaluation of the possible interaction of gastric acid suppressing medication and the EGFR tyrosine kinase inhibitor erlotinib

Objectives

As the bioavailability of erlotinib is dependent on gastric pH, an increase in gastric pH via the concurrent use of gastric acid suppressive medications (AS) may reduce its bioavailability and efficacy. We retrospectively analyzed the BR.21 trial database to pragmatically evaluate the impact of AS use on the median plasma drug levels of erlotinib, adverse events and outcome of participants.

Methods

Monthly median plasma levels of erlotinib were compared between participants utilizing AS and those who did not using a Wilcoxon test. Interaction p-value for AS users and AS non-users was performed using a multivariate Cox model with a time-dependent covariate for AS use. Grade 2 adverse events were compared using Fisher's Exact Test.

Results

The median plasma erlotinib level was not significantly different between AS users and AS non-users, and AS use did not appear to incur a negative impact on PFS or OS (Interaction p-values: PFS p = 0.16; OS p = 0.81). AS users receiving erlotinib had a similar frequency of rash (50.5% vs. 42.0%, p = 0.08) and a statistically higher rate of diarrhea (27.9% vs. 15.6%, p = 0.001) compared to AS non-users. In addition, AS users had higher rates of infections (erlotinib arm: 33.7% vs. 20.0%, p < 0.0001; placebo arm: 22.7% vs. 10.8%, p = 0.02).

Conclusion

This retrospective analysis found that the co-administration of AS and erlotinib did not appear to have a significant impact on the median plasma drug levels or outcome.     

Bevacizumab combined with pemetrexed plus cisplatin followed by maintenance bevacizumab/pemetrexed as first-line treatment of advanced non-squamous non-small cell lung cancer: A single-arm Phase 2 study

Objectives

First-line pemetrexed-cisplatin (Pem-Cis) induction therapy followed by Pem maintenance, and first-line bevacizumab- (Bev-) based therapy are treatment options for patients with advanced non-squamous NSCLC. This study explored efficacy and safety of first-line induction Pem-Cis + Bev followed by maintenance Pem + Bev.

Materials and methods

Patients with ECOG performance status (PS) 0–1 were scheduled to receive four cycles Pem 500 mg/m², Cis 75 mg/m², and Bev 7.5 mg/kg, given every 21 days. In absence of progressive disease (PD) and if ECOG-PS ≤1, patients could continue Pem + Bev maintenance until PD or unacceptable toxicity. All patients received vitamin supplementation as per Pem label. Primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), response rate, and toxicity.

Results

109 patients received induction therapy (median age 61 yrs, ECOG-PS 0/1 54/46%, stage IIIB/IV 9/91%, adenocarcinoma 91%), 72 patients (66.1%) started maintenance therapy. Median (maximum) numbers of cycles were 4 (4) for Cis and 8 (34) for Pem + Bev. Overall, median PFS and OS were 6.9 (90%CI 5.7–8.3) and 14.7 (95%CI 11.5–19.7) months. For patients starting maintenance therapy, median (95%CI) PFS and OS were 9.4 (7.2–11.5) and 19.7 (14.9–25.9) months. Overall response and disease control rates were 42.2% and 67.9%, respectively. Two patients died from study-treatment related toxicity (gastrointestinal hemorrhage, aspiration pneumonia; both during induction therapy). Most common G3/4 toxicities were neutropenia (25.7%) and fatigue (14.7%); hypertension was less common (5.5%).

Conclusion

Patients with advanced NS-NSCLC eligible for Bev-treatment may derive clinical benefit at acceptable toxicity from the addition of Bev to both Pem-Cis induction and Pem maintenance therapy; however, this is not an approved combination regimen.     

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.     

Successful empirical erlotinib treatment of a mechanically ventilated patient newly diagnosed with metastatic lung adenocarcinoma

Background

Lung cancer is the most common solid tumor in critically ill cancer patients who are admitted to intensive care units (ICUs). An ICU trial consists of unlimited ICU support for a limited time period.

Case report

We present the case of a 60-year-old woman with newly diagnosed metastatic lung adenocarcinoma who required mechanical ventilation due to respiratory failure. Empirical erlotinib treatment was administered through a nasogastric feeding tube as part of an ICU trial, which led to a dramatic and durable response.

Conclusion

Empirical erlotinib should be considered when epidermal growth factor receptor (EGFR) mutations are suspected in ICU newly diagnosed patients with lung adenocarcinoma.     

Survival outcome according to KRAS mutation status in newly diagnosed patients with stage IV non-small cell lung cancer treated with platinum doublet chemotherapy

Introduction

Mutations (MT) of the KRAS gene are the most common mutation in non-small cell lung cancer (NSCLC), seen in about 20–25% of all adenocarcinomas. Effect of KRAS MT on response to cytotoxic chemotherapy is unclear.

Methods

We undertook a single-institution retrospective analysis of 93 consecutive patients with stage IV NSCLC adenocarcinoma with known KRAS and EGFR MT status to determine the association of KRAS MT with survival. All patients were treated between January 1, 2008 and December 31, 2011 with standard platinum based chemotherapy at the University of Pennsylvania. Overall and progression free survival were analyzed using Kaplan-Meier and Cox proportional hazard methods.

Results

All patients in this series received platinum doublet chemotherapy, and 42 (45%) received bevacizumab. Overall survival and progression free survival for patients with KRAS MT was no worse than for patients with wild type KRAS. Median overall survival for patients with KRAS MT was 19 months (mo) vs. 15.6 mo for KRAS WT, p = 0.34, and progression-free survival was 6.2 mo in patients with KRAS MT vs. 7mo in patients with KRAS WT, p = 0.51. In multivariable analysis including age, race, gender, and ECOG PS, KRAS MT was not associated with overall survival (HR 1.12, 95% CI 0.58–2.16, p = 0.74) or progression free survival (HR 0.80, 95% CI 0.48–1.34, p = 41). Of note, receipt of bevacizumab was associated with improved overall survival only in KRAS WT patients (HR 0.34, p = 0.01).

Conclusions

KRAS MT are not associated with inferior progression-free and overall survival in advanced NSCLC patients treated with standard first-line platinum-based chemotherapy.     

Retreatment with erlotinib: Regain of TKI sensitivity following a drug holiday for patients with NSCLC who initially responded to EGFR-TKI treatment

Background

Tyrosine kinase inhibitors (TKI) of the epidermal growth factor receptor (EGFR) are approved as treatment of non-small-cell lung cancer (NSCLC). Despite an initially impressive response to EGFR-TKIs, patients with an activating EGFR mutation invariably relapse. For these patients few treatment options are available after additional progression during or after chemotherapy. The aim of this study is to examine the effect of retreatment with an EGFR-TKI after a drug holiday.

Patients and methods

We retrospectively reviewed the medical records of 14 patients with stage IV NSCLC who progressed after long-term disease control with EGFR-TKI, who were subsequently treated with standard chemotherapy and at renewed progression retreated with EGFR-TKI.

Results

Fourteen patients (five male, nine female, median age 55 years (39-70 years) received retreatment with erlotinib. The median interval from the discontinuation of EGFR-TKI to the 2nd episode was 9.5 months (3-36 months). Before starting retreatment 36% (n = 5) had a T790M mutation. Retreatment resulted in 36% (n = 5) partial response, 50% stable disease (n = 7) and 14% progressive disease (n = 2). Among patients with a T790M mutation this number was two, one and two, respectively. Seven patients are still on therapy without signs of progression. Median follow up is 9 months (1.5-16+ months) and median PFS is 6.5 months (1-16+ months).

Conclusion

Our findings suggest that retreatment with erlotinib is an option for patients with NSCLC who initially benefited from previous EGFR-TKI treatment and progressed after standard cytotoxic chemotherapy.     

Epidermal Growth Factor Receptor (EGFR)‐Tyrosine Kinase Inhibitor Treatment and Salvage Chemotherapy in EGFR‐Mutated Elderly Pulmonary Adenocarcinoma Patients

Background.

Lung cancer is frequently a disease of elderly patients. However, these patients are often treated less actively owing to a higher comorbidity rate and poor performance status. The efficacy of different treatments in elderly patients with epidermal growth factor receptor (EGFR)-mutated lung cancer is still unknown.

Materials and Methods.

We retrospectively reviewed the records of our pulmonary adenocarcinoma patients treated between 2010 and 2013. Data on patient age, type of tumor EGFR mutation, response to first-line EGFR-tyrosine kinase inhibitor (TKI) treatment, type of salvage chemotherapy, and efficacy of EGFR-TKI and salvage chemotherapy were collected.

Results.

In all, 473 of 1,230 stage IV adenocarcinoma patients had an EGFR mutation, and 330 of them received first-line TKI treatment. Of the 330 patients, 160 were ≥70 years old (elderly group) and 170 were <70 years old (younger group). The response rate and progression-free survival (PFS) with first-line TKI treatment were not significantly different. The elderly group had shorter median survival. A total of 107 patients received salvage chemotherapy after first-line EGFR-TKI treatment: 45 in the elderly group and 62 in the younger group. Their response rate and PFS were not significantly different; however, the younger group had longer median survival. Additional subgroup analysis showed that younger patients who received platinum-based chemotherapy or combination chemotherapy had better median survival than did the elderly patients. The PFS was longer among younger patients receiving a platinum-based regimen than that among the elderly patients.

Conclusion.

Elderly patients with disease progression after first-line EGFR-TKI treatment can receive chemotherapy and have a response rate similar to that of younger patients.

Implications for Practice:

The aim of the present study was to investigate the efficacy of first-line epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment in elderly patients and the outcomes of subsequent salvage chemotherapy after disease progression. The most important finding was that elderly patients with disease progression after first-line EGFR-TKI treatment can receive salvage chemotherapy and have a response rate similar to that of younger patients who received salvage chemotherapy.     

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.     

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.     

Erlotinib in patients with advanced lung squamous cell carcinoma

Purpose

Erlotinib had proved efficacy in patients with advanced non-small cell lung cancer, especially adenocarcinoma. The aim of this study was to evaluate the efficacy of erlotinib in patients with advanced lung squamous cell carcinoma (LSQC).

Methods

We retrospectively reviewed medical records and serial chest images of consecutive patients who were diagnosed with advanced LSQC and had been treated with erlotinib monotherapy. The primary objective was to evaluate the treatment efficacy and to correlate with patients’ clinical characteristics.

Results

Totally 55 patients were analyzed (42 men and 13 women, median age of 71 years). In 37 patients who had measurable lesions, 6 had partial response and 13 had stable disease, yielding an overall response rate of 16.2 % and disease control rate of 51.4 %. In all patients, the median progression-free survival (PFS) and overall survival (OS) were 2.0 months (95 % confidence interval, 1.5–2.4 months) and 10.4 months (95 % confidence interval, 0.6–20.2 months), respectively. The PFS and OS were significantly longer in patients who had good clinical response (either the tumor achieved partial response or the patients had disease controlled for more than 6 months) than those who did not (median PFS, 13.0 vs. 1.6 months; median OS, 28.3 vs. 4.9 months; both P values <0.01). Patients who never smoked seemed to have better clinical response and longer survival than those who had smoking history (P = 0.077 and 0.086, respectively).

Conclusions

Erlotinib could provide some clinical benefit to patients with advanced LSQC.     

Impact of cigarette smoking on response to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors in lung adenocarcinoma with activating EGFR mutations

Objectives

The aim of this study is to evaluate the predictive impact of cigarette smoking on treatment outcomes of EGFR-tyrosine kinase inhibitors (TKIs) in lung adenocarcinoma patients with activating EGFR mutations.

Methods

We retrospectively analyzed 222 consecutive recurrent or unresectable lung adenocarcinoma patients who harbored activating EGFR mutations (exon 19 deletion or exon 21 L858R) and had received gefitinib or erlotinib. Detailed smoking histories were obtained from all patients according to a standard protocol.

Results

Of 222 EGFR-mutated patients, 65.3% were never-smokers, 19.8% were smokers with <30 pack-years, and 14.9% were smokers with ≥30 pack-years smoking dosage. The disease control rate (DCR) and objective response rate (ORR) of smokers with ≥30 pack-years were significantly lower than never-smokers and smokers with <30 pack-years (DCR, 78.8% vs. 93.1%, p = 0.016; ORR, 45.5% vs. 62.4%, p = 0.020). Smokers with ≥30 pack-years showed significantly shorter PFS than never-smokers (6.4 vs. 11.8 months, p = 0.001) and smokers with <30 pack-years (6.4 vs. 11.4 months, p = 0.033), as well as shorter overall survival from the time of metastatic diagnosis than never-smokers (33.6 vs. 46.2 months, p = 0.003). There was no survival difference between smokers with <30 pack-year and never smokers. In the multivariate analysis adjusted for age, sex, performance status, initial stage, and line of EGFR-TKI, the presence of smoking dosage ≥30 pack-years was an independent predictive factor for the disease progression to EGFR-TKIs (hazard ratio, 1.87; 95% confidence interval, 1.15–3.05; p = 0.012).

Conclusions

Cigarette smoking dosage of ≥30 pack-years is an independent negative predictive factor of EGFR-TKI treatment outcome in lung adenocarcinoma patients with activating EGFR mutations.     

Feasibility and effectiveness of trifluridine/tipiracil in metastatic colorectal cancer: real-life data from The Netherlands

Background

The RECOURSE trial showed clinical efficacy for trifluridine/tipiracil for refractory metastatic colorectal cancer patients. We assessed the feasibility and effectiveness of trifluridine/tipiracil in daily clinical practice in The Netherlands.

Methods

Medical records of patients from 17 centers treated in the trifluridine/tipiracil compassionate use program were reviewed and checked for RECOURSE eligibility criteria. Baseline characteristics, safety, and survival times were compared, and prespecified baseline characteristics were tested in multivariate analyses for prognostic significance on overall survival (OS).

Results

A total of 136 patients with a median age of 62 years were analyzed. Forty-three patients (32%) did not meet the RECOURSE eligibility criteria for not having received all prior standard treatments (n = 35, 26%) and/or ECOG performance status (PS) 2 (n = 12, 9%). The most common grade ≥3 toxicities were neutropenia (n = 44, 32%), leukopenia (n = 8, 6%), anemia (n = 7, 5%), and fatigue (n = 7, 5%). Median progression-free survival (PFS) and median OS were 2.1 (95% CI, 1.8–2.3) and 5.4 months (95% CI, 4.0–6.9), respectively. Patients with ECOG PS 2 had a worse median OS (3.2 months) compared to patients with ECOG PS 0–1 (5.9 months). ECOG PS, KRAS-mutation status, white blood cell count, serum lactate dehydrogenase, and alkaline phosphatase were prognostic factors for OS.

Conclusions

Our data show that treatment with trifluridine/tipiracil in daily clinical practice is feasible and safe. Differences in patient characteristics between our population and the RECOURSE study population should be taken into account in the interpretation of survival data. Our results argue against the use of trifluridine/tipiracil in patients with ECOG PS 2.

Funding

Johannes J.M. Kwakman received an unrestricted research grant from Servier.

     

Radical pleurectomy/decortication followed by high dose of radiation therapy for malignant pleural mesothelioma. Final results with long-term follow-up

Purpose

We have previously shown the feasibility of delivering high doses of radiotherapy in malignant pleural mesothelioma (MPM) patients who underwent radical pleurectomy/decortication (P/D) or surgical biopsy. In this report, we present the long-term results of MPM patients treated with radical P/D followed by high doses of radiotherapy.

Methods and materials

Twenty consecutive MPM patients were enrolled in this prospective study and underwent radical P/D followed by high dose radiotherapy. The clinical target volume was defined as the entire hemithorax excluding the intact lung. The dose prescribed was 50 Gy in 25 fractions. Any FDG-avid areas or regions of particular concern for residual disease were given a simultaneous boost to 60 Gy. Nineteen patients received cisplatin/pemetrexed chemotherapy. Kaplan–Meier analysis was used to calculate rates of overall survival (OS), progression-free survival (PFS), and loco-regional control (LRC).

Results

The median follow-up was of 27 months. The median OS and PFS were 33 and 29 months, respectively. The median LRC was not reached. The Kaplan–Meier estimates of OS at 2 and 3 years were 70% and 49%, respectively. The estimates of PFS at 2 and 3 years were 65% and 46%, respectively. The estimates of LRC at 2 and 3 years were 68% and 59%, respectively. The predominant pattern of failure was distant: 7 patients developed distant metastases as the first site of relapse, whereas only 3 patients experienced an isolated loco-regional recurrence. No fatal toxicity was reported. Five Grades 2–3 pneumonitis were documented.

Conclusions

High dose radiation therapy following radical P/D led to excellent loco-regional control and survival results in MPM patients. A median OS of 33 months and a 3-year OS rate of 49% are among the best observed in recent studies, supporting the idea that this approach represents a concrete therapeutic option for malignant pleural mesothelioma.     

Expression of estrogen receptor beta predicts a clinical response and longer progression-free survival after treatment with EGFR-TKI for adenocarcinoma of the lung

Purpose

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (EGFR-TKI) demonstrates a dramatic clinical response for the lung adenocarcinoma patients harboring a somatic mutation of EGFR. Such EGFR mutations are frequently found in adenocarcinoma with a strong expression of estrogen receptor (ER) beta, which has been shown to correlate with a favorable prognosis for the patients with EGFR mutations. The aim of this study is to elucidate the correlation between expression of ER beta and the therapeutic effect of EGFR-TKI in adenocarcinoma of the lung.

Patients and methods

Forty-three patients who were treated with EGFR-TKI for adenocarcinoma of the lung were evaluated. The expression of ER beta and the EGFR mutation were evaluated by immunohistochemistry and the polymerase chain reaction, respectively. Patients divided into two groups by the nuclear expression of ER beta. The clinical response and survival data were compared between the two groups.

Result

Strong (S) and weak (W) expression of ER beta was observed in 21 and 22 patients, respectively. EGFR mutations were detected in 30 (69.8%) cases. The S group had more frequent EGFR mutations than the W group (85.7%, 54.5%, p = 0.045). The S group had better response rate (p = 0.006) and longer progression-free survival (PFS; p = 0.001) than the W group. Even in a limited analysis in the patients with EGFR mutations, the S group had tended to have a better response rate (77.8%, 41.7%, p = 0.063), and significant longer PFS (p = 0.012) than the W group.

Conclusion

A strong expression of ER beta predicts a good clinical outcome for patients with adenocarcinoma of the lung after treatment with EGFR-TKI. This suggests that the expression status of ER beta can be a candidate surrogate marker for EGFR-TKI treatment of patients with adenocarcinoma of the lung. Further investigation will be necessary to identify biomarkers using a larger cohort of patients in a prospective study.