Gefitinib and erlotinib can penetrate into the central nervous system (CNS) and elicit responses in patients with brain metastases (BM) from non-small cell lung cancer (NSCLC). However, there are ...incomplete data about their impact on the development and control of CNS metastases.
Patients with stage IIIB/IV NSCLC with somatic EGFR mutations initially treated with gefitinib or erlotinib were identified. The cumulative risk of CNS progression was calculated using death as a competing risk.
Of the 100 patients, 19 had BM at the time of diagnosis of advanced NSCLC; 17 of them received CNS therapy before initiating gefitinib or erlotinib. Eighty-four patients progressed after a median potential follow-up of 42.2 months. The median time to progression was 13.1 months. Twenty-eight patients developed CNS progression, 8 of whom had previously treated BM. The 1- and 2-year actuarial risk of CNS progression was 7% and 19%, respectively. Patient age and EGFR mutation genotype were significant predictors of the development of CNS progression. The median overall survival for the entire cohort was 33.1 months.
Our data suggest a lower risk of CNS progression in patients with advanced NSCLC and somatic EGFR mutations initially treated with gefitinib or erlotinib than published rates of 40% in historical series of advanced NSCLC patients. Further research is needed to distinguish between the underlying rates of developing CNS metastases between NSCLC with and without EGFR mutations and the impact of gefitinib and erlotinib versus chemotherapy on CNS failure patterns in these patients.
Purpose: Somatic mutations in the epidermal growth factor receptor (EGFR) have been detected in patients with non–small cell lung
cancer (NSCLC) and are associated with sensitivity to treatment with ...gefitinib or erlotinib. Our study explored the relationship
between the two most common types of somatic EGFR mutations, exon 19 deletions and the L858R point mutation, and outcomes
of patients following treatment with gefitinib or erlotinib.
Experimental Design: Tumor specimens obtained before treatment with gefitinib or erlotinib were analyzed for EGFR mutations. Patients with exon
19 deletion or L858R mutations were identified. The response rate, time to progression, and overall survival were determined
for the two groups.
Results: We identified 36 patients with NSCLC and an EGFR mutation who were treated with gefitinib or erlotinib. Patients with an
exon 19 deletion had a significantly longer overall survival compared with patients with an L858R mutation (38 versus 17 months;
P = 0.04). There were also trends toward higher response rate (73% versus 50%) and improved time to progression (24 versus
10 months) for the patients with an exon 19 deletion, although these were not independently significant in a multivariate
analysis. A difference in response rate for patients treated with gefitinib compared with erlotinib was also noted 18 of
23 (78%) versus 3 of 9 (33%); P = 0.04. No obvious difference in time to progression or overall survival was noted between gefitinib- and erlotinib-treated
patients.
Conclusions: Patients with NSCLC and EGFR exon 19 deletions have a longer survival following treatment with gefitinib or erlotinib compared
with those with the L858R mutation. Pooling of greater numbers of patients and completion of prospective trials are needed
to further define the predictive and prognostic roles of different EGFR mutations with respect to treatment with gefitinib,
erlotinib, and other EGFR inhibitors.
LKB1 loss is common in lung cancer, but no assay exists to efficiently evaluate the presence or absence of LKB1. We validated an IHC assay for LKB1 loss and determined the impact of LKB1 loss in ...KRAS-mutant non-small cell lung cancer (NSCLC).
We optimized and validated an IHC assay for LKB1 (clone Ley37D/G6) using a panel of lung cancer cell lines and tumors with known LKB1 mutations, including 2 patients with Peutz-Jeghers syndrome (PJS) who developed lung adenocarcinoma. We retrospectively analyzed tumors for LKB1 using IHC from 154 KRAS-mutant NSCLC patients, including 123 smokers and 31 never-smokers, and correlated the findings with patient and tumor characteristics and clinical outcome.
LKB1 expression was lost by IHC in 30% of KRAS-mutant NSCLC (smokers 35% vs. never-smokers 13%, P = 0.017). LKB1 loss did not correlate with a specific KRAS mutation but was more frequent in tumors with KRAS transversion mutations (P = 0.029). KRAS-mutant NSCLC patients with concurrent LKB1 loss had a higher number of metastatic sites at the time of diagnosis (median 2.5 vs. 2, P = 0.01), higher incidence of extrathoracic metastases (P = 0.01), and developed brain metastasis more frequently (48% vs. 25%, P = 0.02). There was a nonsignificant trend to worse survival in stage IV KRAS-mutant NSCLC patients with LKB1 loss.
LKB1 IHC is a reliable and efficient assay to evaluate for loss of LKB1 in clinical samples of NSCLC. LKB1 loss is more common in smokers, and is associated with a more aggressive clinical phenotype in KRAS-mutant NSCLC patients, accordingly to preclinical models.
This is a phase II, multicenter, open-label study of chemotherapy-naïve patients with non-small-cell lung cancer (NSCLC) and age > or = 70 years who were treated with erlotinib and evaluated to ...determine the median, 1-year, and 2-year survival. The secondary end points include radiographic response rate, time to progression (TTP), toxicity, and symptom improvement.
Eligible patients with NSCLC were treated with erlotinib 150 mg/d until disease progression or significant toxicity. Tumor response was assessed every 8 weeks by computed tomography scan using Response Evaluation Criteria in Solid Tumors. Tumor samples were analyzed for the presence of somatic mutations in EGFR and KRAS.
Eighty eligible patients initiated erlotinib therapy between March 2003 and May 2005. There were eight partial responses (10%), and an additional 33 patients (41%) had stable disease for 2 months or longer. The median TTP was 3.5 months (95% CI, 2.0 to 5.5 months). The median survival time was 10.9 months (95% CI, 7.8 to 14.6 months). The 1- and 2- year survival rates were 46% and 19%, respectively. The most common toxicities were acneiform rash (79%) and diarrhea (69%). Four patients developed interstitial lung disease of grade 3 or higher, with one treatment-related death. EGFR mutations were detected in nine of 43 patients studied. The presence of an EGFR mutation was strongly correlated with disease control, prolonged TTP, and survival.
Erlotinib monotherapy is active and relatively well tolerated in chemotherapy-naïve elderly patients with advanced NSCLC. Erlotinib merits consideration for further investigation as a first-line therapeutic option in elderly patients.
Purpose.
Epidermal growth factor receptor (EGFR)‐mutant non‐small cell lung cancer has an oncogene‐addicted biology that confers sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Published data ...suggest that EGFR addiction persists after development of TKI acquired resistance, leading many clinicians to continue TKI with subsequent chemotherapy; however, this strategy has not been formally evaluated.
Methods.
We retrospectively reviewed an institutional database to identify patients with advanced EGFR mutation with acquired resistance who subsequently received chemotherapy. Patients were classified as receiving chemotherapy with continued erlotinib or chemotherapy alone. We assessed differences in outcomes between the two strategies.
Results.
Seventy‐eight patients were included, 34 treated with chemotherapy and erlotinib and 44 treated with chemotherapy alone. Objective response rate was evaluable in 57 patients and was 41% for those treated with chemotherapy and erlotinib and 18% for those treated with chemotherapy alone. After adjusting for chemotherapy regimen and length of initial TKI course, the odds ratio for the response rate was 0.20 (95% confidence interval: 0.05–0.78; p = .02) favoring treatment with chemotherapy and erlotinib. The median progression‐free survival was 4.4 months on chemotherapy and erlotinib and 4.2 months on chemotherapy alone (adjusted hazard ratio = 0.79; 95% confidence interval: 0.48–1.29; p = .34). There was no difference in overall survival.
Conclusion.
This is the first study, to our knowledge, to demonstrate that continuation of EGFR TKI with chemotherapy in patients with acquired resistance improves outcomes compared with chemotherapy alone. We observed an improved response rate but no difference in progression‐free survival or overall survival. A larger prospective clinical trial is needed to evaluate this promising strategy further.
摘要
目的。表皮生长因子受体 (EGFR) 突变型非小细胞肺癌存在致癌基因依赖性特点，这使得它对 EGFR 酪氨酸激酶抑制剂 (TKI) 具有很高的敏感性。已发表的数据表明，即使当癌灶产生 TKI 获得性耐药后，它仍旧对 EGFR 致癌基因存在依赖性，所以很多临床医生后续化疗时选择继续使用 TKI。但是，这一策略尚未得到正式评估。
方法。通过对一个机构数据库进行回顾性评估，我们找出了那些在产生获得性耐药后又继续接受化疗的晚期 EGFR 突变型非小细胞肺癌患者。我们将这些患者分为两组：厄洛替尼联合化疗组和单纯化疗组。然后对两种策略的转归差异进行了评估。
结果。本研究共纳入了 78 名患者，其中 34 名接受了厄洛替尼联合化疗，44 名接受了单纯化疗。有 57 名患者可进行客观见效率评价。结果显示，厄洛替尼联合化疗组的客观见效率为 41%，而单纯化疗组的客观见效率为 18%。经校正化疗方案及初始 TKI 疗程后，两组的见效率比值比为 0.20（95% 置信区间：0.05‐0.78；p = 0.02），表明厄洛替尼联合化疗的效果优于单纯化疗。厄洛替尼联合化疗组的中位无进展生存期为 4.4 个月，而单纯化疗组则为 4.2 个月（校正后风险比 = 0.79；95% 置信区间：0.48 –1.29；p = 0.34）。总体生存期并无显著差异。
结论。据我们所知，本研究是第一次证实，对已产生获得性耐药的患者继续进行 EGFR TKI 联合化疗与进行单纯化疗相比更有助于改善患者的预后。我们观察到，患者的见效率有所改善，但无进展生存期或总体生存期并无显著差异。我们需要通过更大规模的前瞻性临床试验来进一步评估这一充满希望的治疗策略。The Oncologist 2013;18:1214–1220
Published data suggest that epidermal growth factor receptor (EGFR) addiction persists after development of acquired resistance to an EGFR tyrosine kinase inhibitor (TKI), leading many clinicians to continue the TKI with subsequent chemotherapy; however, this strategy has not been formally evaluated. We retrospectively reviewed an institutional database and identified 78 patients with advanced EGFR‐mutation with acquired resistance who subsequently received chemotherapy; 34 were treated with chemotherapy and erlotinib and 44 were treated with chemotherapy alone. This study demonstrates that continuation of EGFR TKI with chemotherapy in patients with acquired resistance improves outcomes compared with switching to chemotherapy alone.
This retrospective study was undertaken to investigate the impact of initial gefitinib or erlotinib (EGFR tyrosine kinase inhibitor, EGFR-TKI) versus chemotherapy on the risk of central nervous ...system (CNS) progression in advanced non-small cell lung cancer (NSCLC) with EGFR mutations.
Patients with stage IV or relapsed NSCLC with a sensitizing EGFR mutation initially treated with gefitinib, erlotinib, or chemotherapy were identified. The cumulative risk of CNS progression was calculated using death as a competing risk.
One hundred and fifty-five patients were eligible (EGFR-TKI: 101, chemotherapy: 54). Twenty-four patients (24%) in the EGFR-TKI group and 12 patients (22%) in the chemotherapy group had brain metastases at the time of diagnosis of advanced NSCLC (P = 1.000); 32 of the 36 received CNS therapy before initiating systemic treatment. Thirty-three patients (33%) in the EGFR-TKI group and 26 patients (48%) in the chemotherapy group developed CNS progression after a median follow-up of 25 months. The 6-, 12-, and 24-month cumulative risk of CNS progression was 1%, 6%, and 21% in the EGFR-TKI group compared with corresponding rates of 7%, 19%, and 32% in the chemotherapy group (P = 0.026). The HR of CNS progression for upfront EGFR-TKI versus chemotherapy was 0.56 95% confidence interval (CI), 0.34-0.94.
Our data show lower rates of CNS progression in EGFR-mutant advanced NSCLC patients initially treated with an EGFR-TKI compared with upfront chemotherapy. If validated, our results suggest that gefitinib and erlotinib may have a role in the chemoprevention of CNS metastases from NSCLC.
There are few effective treatment options for leptomeningeal metastasis (LM) in non-small-cell lung cancer (NSCLC). This study assessed the feasibility of high-dose gefitinib in patients with LM from ...NSCLC harboring EGFR mutations or prior systemic response to EGFR-TKI.
This phase I open-label trial of a novel gefitinib dosing schedule employed a 3+3 design. Eligible NSCLC patients with LM had known EGFR mutations and/or prior response to EGFR-TKI. Patients alternated 2 weeks of high-dose daily gefitinib (dose levels: 750 mg, 1000 mg, 1250 mg) with 2 weeks of maintenance therapy (500 mg daily). Primary endpoints were safety and toxicity. Secondary endpoints included overall survival (OS), neurological progression-free survival, radiological response, and cytological response in cerebrospinal fluid (CSF).
Seven patients were treated: 3 at 750 mg dose level, 4 at 1000 mg dose level. There were no DLTs at the 750 mg dose level, and one DLT (toxic epidermal necrolysis) at the 1000 mg dose level. The study was closed due to slow accrual. Median neurological PFS was 2.3 months (range 1.6-4.0 months); median OS was 3.5 months (range 1.6-5.1 months). Though there were no radiologically documented remissions of LM disease, four patients had improvement in neurological symptoms. One patient cleared their CSF of NSCLC cells, while 2 others had decrease in malignant cells in CSF.
Although the MTD was not defined due to slow accrual, this study provides important information about the tolerability and CSF penetration of high-dose gefitinib as a therapeutic option for modest palliation for NSCLC patients with LM and a known EGFR mutation.
The purpose of this article is to compare the recently published revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1) to the original guidelines (RECIST 1.0) for ...advanced non-small cell lung cancer (NSCLC) after erlotinib therapy and to evaluate the impact of the new CT tumor measurement guideline on response assessment.
Forty-three chemotherapy-naive patients with advanced NSCLC treated with erlotinib in a single-arm phase 2 multicenter open-label clinical trial were retrospectively studied. CT tumor measurement records using RECIST 1.0 that were generated as part of the prospective clinical trial were reviewed. A second set of CT tumor measurements was generated from the records to meet RECIST 1.1 guidelines. The number of target lesions, best response, and time to progression were compared between RECIST 1.1 and RECIST 1.0.
The number of target lesions according to RECIST 1.1 decreased in 22 patients (51%) and did not change in 21 patients (49%) compared with the number according to RECIST 1.0 (p < 0.0001, paired Student's t test). Almost perfect agreement was observed between best responses using RECIST 1.1 and RECIST 1.0 (weighted kappa = 0.905). Two patients with stable disease according to RECIST 1.0 had progressive disease according to RECIST 1.1 criteria because of new lesions found on PET/CT. There was no significant difference in time to progression between RECIST 1.1 and RECIST 1.0 (p = 1.000, sign test).
RECIST 1.1 provided almost perfect agreement in response assessment after erlotinib therapy compared with RECIST 1.0. Assessment with PET/CT was a major factor that influenced the difference in best response assessment between RECIST 1.1 and RECIST 1.0.
Highlights • Early response assessment of chemoradiation can guide clinical-decision making. • Volume change after chemoradiation is associated with pathological response for NSCLC. • Volume change ...is further associated with prediction of locoregional control. • Association with pathologic response is significant in the IIIa subgroup. • RECIST response not associated with pathologic response or locoregional control
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