晚期NSCLC靶向和化疗方案选择的几个问题

老马 · 发表于 2014-1-5 02:29:22

http://www.ncbi.nlm.nih.gov/pubmed/21784628
Eur J Cancer. 2011 Nov;47(17):2603-6. doi: 10.1016/j.ejca.2011.06.046. Epub 2011 Jul 23.
Retreatment with erlotinib: Regain of TKI sensitivity following a drug holiday for patients with NSCLC who initially responded to EGFR-TKI treatment.
Becker A, Crombag L, Heideman DA, Thunnissen FB, van Wijk AW, Postmus PE, Smit EF.
Author information Department of Pulmonary Diseases, VU University Medical Center, De Boelelaan 1117, Amsterdam, The Netherlands. a.becker@vumc.nl
Abstract
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.

老马 · 发表于 2014-1-5 02:31:34

http://www.ncbi.nlm.nih.gov/pubmed/21194487
BMC Cancer. 2011 Jan 1;11:1. doi: 10.1186/1471-2407-11-1.
Clinical responses to EGFR-tyrosine kinase inhibitor retreatment in non-small cell lung cancer patients who benefited from prior effective gefitinib therapy: a retrospective analysis.
Watanabe S, Tanaka J, Ota T, Kondo R, Tanaka H, Kagamu H, Ichikawa K, Koshio J, Baba J, Miyabayashi T, Narita I, Yoshizawa H.
Author information Department of Medicine, Niigata University Medical and Dental Hospital, Niigata City, Japan. satoshimd@yahoo.co.jp

Abstract
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.

老马 · 发表于 2014-1-5 02:32:57

http://www.ncbi.nlm.nih.gov/pubmed/23991294
J Thorac Dis. 2013 Aug;5(4):400-5. doi: 10.3978/j.issn.2072-1439.2013.07.28.
Re-administration after the failure of gefitinib or erlotinib in patients with advanced non-small cell lung cancer.
Song Z, Yu X, He C, Zhang B, Zhang Y.
Author information Department of Chemotherapy, Zhejiang Cancer Hospital, Hangzhou 310022, China; ; Key Laboratory Diagnosis and Treatment Technology on Thoracic Oncology, Hangzhou 310022, China.
Abstract
OBJECTIVE: Few treatment options are available for advanced non-small cell lung cancer (NSCLC) patients who have failed of gefitinib or erlotinib treatment in second/third-line treatment. The aim of this study was to investigate the efficacy of re-administration of the same TKI after failure of gefitinib or erlotinib.

PATIENTS AND METHODS: The clinical data of 33 patients with advanced NSCLC were retrospectively analyzed. All of the patients were given the same TKI treatment after the failure of gefitinib or erlotinib. Survival analysis was evaluated by Kaplan-Meier method.

RESULTS: Twenty patients (60.6%) were re-administration with gefitinib as the 2(nd) EGFR-TKI, and thirteen patients (39.4%) received erlotinib. One patient (3.0%) showed partial response (PR), 14 (42.4%) achieved stable disease (SD), and 18 (54.5%) had progressive disease (PD). The disease control rate was 45.5% and the median progression-free survival was 1.5 months (95% CI: 0.6-2.3 months). The PFS in patients who got disease control in the prior TKI was 2.2 and 1.2 months in the progression disease cases (P=0.29), the DCR was 54.5% and 27.3% in two group, respectively (P=0.26).

CONCLUSIONS: Re-administration of TKI seems to be a potential therapeutic option for treatment of selected advanced NSCLC patients after failure of geﬁtinib or erlotinib, especially for the patients with NSCLC who once responded from the prior TKI treatment.

老马 · 发表于 2014-1-5 02:40:26

http://www.nature.com/nrclinonc/journal/v10/n10/index.html
Drug rechallenge and treatment beyond progression—implications for drug resistance
Elizabeth A. Kuczynski, Daniel J. Sargent, Axel Grothey & Robert S. Kerbel
p571 | doi:10.1038/nrclinonc.2013.158
There are many circumstances where patients respond to reintroduction of the same therapy (drug rechallenge) following relapse or disease progression during therapy, and in a few cases, when a therapy is continued beyond disease progression. The authors comprehensively describe the available data on rechallenge and continuation beyond progression treatment strategies, discuss the potential mechanisms explaining tumour re-sensitization with reintroduced or continued therapy, and make the case for why drug resistance definitions need to be re-evaluated.

老马 · 发表于 2014-1-5 03:14:02

Pathol Oncol Res. 2013 Oct;19(4):833-8. doi: 10.1007/s12253-013-9651-z. Epub 2013 May 29.
Disease flare after EGFR tyrosine kinase inhibitor cessation predicts poor survival in patients with non-small cell lung cancer.
Chen HJ, Yan HH, Yang JJ, Chen ZH, Su J, Zhang XC, Wu YL.
Author information Division of Pulmonary Oncology, Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China.

Abstract
Available study revealed non-small cell lung cancer (NSCLC) patients faced a risk of disease flare after cessation of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment. There was no data concerning the prognostic value of disease flare. This study aimed to investigate the prevalence of disease flare in a Chinese cohort, and analyzed its prediction to survival. A cohort of 227 NSCLC patients with acquired resistance to EGFR TKI was retrospectively analyzed. Prevalence and clinical features of disease flare after TKI cessation were reviewed. Survival data were analyzed between patients with flare and those without flare. EGFR gene mutations in tumors were detected. Twenty of 227 (8.8 %) patients were determined with disease flare after TKI cessation. The median interval from TKI cessation to disease flare was 7 days (range 3-18). Forty percent of patients complained of deteriorated dyspnea attributable to malignant effusion. Thirty percent of patients had progressive lesions in the brain. After TKI cessation 35 % of flare patients died before challenge of subsequent treatment. No response was observed in 30 % of flare patients undergoing subsequent chemotherapy. When compared with the non-flare group, patients with disease flare demonstrated comparable progression-free survival (10.1 vs. 9.9 months; P = 0.973), shorter post-TKI survival (4.1 vs. 6.1 months; P < 0.001), and a significantly poor overall survival (16.6 vs. 21.6 months; P = 0.002). Disease flare after cessation of EGFR TKI occurred in Chinese NSCLC population and predicted a poor survival.

http://www.ncbi.nlm.nih.gov/pubmed/23716023

老马 · 发表于 2014-1-5 03:31:49

Lung Cancer. 2013 Apr;80(1):1-4. doi: 10.1016/j.lungcan.2012.12.019. Epub 2013 Jan 10.
Transformation to "high grade" neuroendocrine carcinoma as an acquired drug resistance mechanism in EGFR-mutant lung adenocarcinoma.
Popat S, Wotherspoon A, Nutting CM, Gonzalez D, Nicholson AG, O'Brien M.
Author information Royal Marsden Hospital NHS Foundation Trust, London, and Surrey, UK. sanjay.popat@rmh.nhs.uk

Abstract
Several different acquired resistance mechanisms of EGFR mutant lung adenocarcinoma to EGFR-tyrosine kinase inhibitor (TKI) therapy have been described, most recently transformation to small cell lung carcinoma (SCLC). We describe the case of a 46-year-old female with relapsed EGFR exon 19 deletion lung adenocarcinoma treated with erlotinib, and on resistance, cisplatin-pemetrexed. Liver rebiopsy identified an afatinib-resistant combined SCLC and non-small cell carcinoma with neuroendocrine morphology, retaining the EGFR exon 19 deletion. This case highlights acquired EGFR-TKI resistance through transformation to the high-grade neuroendocrine carcinoma spectrum and that that such transformation may not be evident at time of progression on TKI therapy.
http://www.ncbi.nlm.nih.gov/pubmed/23312887