ASCO2013摘要

Phase I and pharmacodynamic study of the histone deacetylase (HDAC) inhibitor romidepsin plus erlotinib in previously treated advanced non-small cell lung cancer (NSCLC).
Subcategory:
Metastatic Non-small Cell Lung Cancer
Category:
Lung Cancer - Non-small Cell Metastatic
Meeting:
2013 ASCO Annual Meeting
Session Type and Session Title:
General Poster Session, Lung Cancer - Non-small Cell Metastatic
Abstract Number:
8088^

Citation:
J Clin Oncol 31, 2013 (suppl; abstr 8088^)

Author(s):
David E. Gerber, Rachael Skelton, Ying Dong, Laurin Loudat, Jonathan Dowell, David A. Boothman, Venetia Sarode, Wei Zhang, Yang Xie, Adi Gazdar, Eugene P. Frenkel, Joan H. Schiller; Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX; Harold C. Simmons Cancer Center, Univesity of Texas Southwestern Medical Center, Dallas, TX



Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).

Abstract Disclosures

Abstract:


Background: Preclinical studies have demonstrated anti-tumor efficacy of the combination of the HDAC inhibitor romidepsin plus erlotinib in NSCLC models insensitive to erlotinib monotherapy (eg, KRAS mutation, EGFR resistance mutation, EGFR wild type). Methods: This phase I study evaluated safety, pharmacodynamics, and preliminary activity of romidepsin (8-10 mg/m2) given IV days 1, 8, and 15 every 28 days plus erlotinib 150 mg PO daily in previously treated advanced NSCLC. In Cycle 1, erlotinib was initiated on Day 3, permitting pharmacodynamic analysis of romidepsin alone and in combination. Results: As of January 31, 2013, 15 patients (pts) have been treated: median age 60 years; 7 F, 8 M; all former or current smokers; 6 had prior erlotinib exposure; 8 adenocarcinoma, 6 squamous, 1 large cell; 5 EGFR wild type 1 KRAS mutation, 9 unknown mutation status. Most common related AEs regardless of grade were nausea (87%), vomiting (73%), fatigue (60%), diarrhea and rash (both 53%), and decreased appetite (47%). Grade 3-4 AEs (all grade 3) included nausea and vomiting (both 20%); decreased appetite, diarrhea, fatigue (each 13%). Dose-limiting nausea and vomiting occurred at romidepsin 10 mg/m2 level despite aggressive antiemetic prophylaxis and treatment. At romidepsin 8 mg/m2, related grade 3 AEs included fatigue (n=1) and diarrhea (n=1), with no grade 3 nausea or vomiting. 9 pts were evaluable by RECIST; best response SD (n=6), PD (n=3). Median PFS was 3.3 months (range 1.4-16.5 months). At romidepsin 8 mg/m2, PFS range 2.0-16.5 months. At both dose levels, romidepsin inhibited HDAC activity and increased histone H3 and H4 acetylation status in peripheral blood mononuclear cells. Romidepsin also inhibited EGFR phosphorylation and, in 60% of pts, MAPK phosphorylation in skin biopsies. Conclusions: Romidepsin 8 mg/m2 plus erlotinib appears well tolerated, has encouraging evidence of disease control, and exhibits effects on relevant molecular targets in an unselected advanced NSCLC population. Further studies are underway. Clinical trial information: NCT01302808.

KRAS subset analysis from randomized phase II trials of erlotinib versus erlotinib plus sorafenib or pazopanib in refractory non-small cell lung cancer (NSCLC).
Subcategory:
Metastatic Non-small Cell Lung Cancer
Category:
Lung Cancer - Non-small Cell Metastatic
Meeting:
2013 ASCO Annual Meeting
Session Type and Session Title:
General Poster Session, Lung Cancer - Non-small Cell Metastatic
Abstract Number:
8091

Citation:
J Clin Oncol 31, 2013 (suppl; abstr 8091)

Author(s):
David Michael Waterhouse, Dawn Michelle Stults, Davey B. Daniel, Paula L. Griner, F Anthony Greco, Howard A. Burris, John D. Hainsworth, David R. Spigel; Oncology Hematology Care/SCRI, Cincinnati, OH; Sarah Cannon Research Institute, Nashville, TN; Tennessee Oncology, PLLC/SCRI, Nashville, TN; Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN



Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).

Abstract Disclosures

Abstract:


Background: KRAS mutations are among the most common genetic alterations in NSCLC; however no targeted therapies have been approved to benefit this lung cancer subset. Between 2/2008 and 2/2011 our center conducted two consecutive multicenter randomized phase II trials in patients (pts) with refractory NSCLC comparing erlotinib/placebo versus erlotinib + either sorafenib or pazopanib, both oral multikinase inhibitors (Spigel et al, JCO 2011; Chicago MSTO 2012). Progression-free survival (PFS) was improved with the multikinase regimens in the EGFR wild-type (WT) subsets, but not in the overall populations. An unplanned analysis of the combined KRAS subset data is the subject of this report. Methods: Eligibility criteria for both trials included: stage IIIB/IV NSCLC; 1 to 2 prior regimens; ECOG performance status 0–2; measurable disease. PFS was the primary endpoint of each trial. Treatment groups included: erlotinib/placebo (N=121), erlotinib/sorafenib (N=112), and erlotinib/pazopanib (N=127). 168 pts (47%) in these three groups had sufficient tumor specimens for KRAS analysis. Results: The PFS and OS results based on KRAS results are shown in the Table below. Conclusions: Patients in whom the KRAS mutation status was known achieved a significantly longer PFS with erlotinib and a multikinase inhibitor than with erlotinib alone. Although this unplanned combined analysis has several limitations, the greater PFS and OS benefits in pts with KRAS mutations warrant further study. Clinical trial information: NCT00600015; NCT01027598.

Effect of sequential chemotherapy and gefitinib on survival outcome in advanced NSCLC with acquired gefitinib resistance.
Subcategory:
Metastatic Non-small Cell Lung Cancer
Category:
Lung Cancer - Non-small Cell Metastatic
Meeting:
2013 ASCO Annual Meeting
Session Type and Session Title:
This abstract will not be presented at the 2013 ASCO Annual Meeting but has been published in conjunction with the meeting.
Abstract Number:
e19085

Citation:
J Clin Oncol 31, 2013 (suppl; abstr e19085)

Author(s):
Wang Huijuan, Zhang Mina, Zhang guo Wei, Zhu Hui, Wang Qiming, Li Peng, Yan Xiangtao, Li Shaomei, Ma Zhi Yong; Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China



Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).

Abstract Disclosures

Abstract:


Background: As one of the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), gefitinib has been proven to be highly effective for patients with advanced NSCLC. However, almost all patients who experienced remarkable improvement eventually develop acquired resistance. There are no approved therapies after disease progression on gefitinib. Subsequent therapeutic modalities are needed. Methods: From September 2007 to July 2012, 74 patients with pathologically confirmed advanced NSCLC who had had disease control with gefitinib more than 6 months were retrospectively reviewed. After acquired resistance to gefitinib, 38 (51%) patients received systemic chemotherapy and sequential gefitinib, 14 (20%) received local treatment and continued gefitinib, and 22 (29%) received best supportive care (BSC) only.Our objective was to assess the survival outcome of different subsequent therapy after acquired resistance to gefitinib. Results: In chemotherapy group, Patients achieved higher response rate and disease control rate, respectively 39% and 82%. The median overall survival (OS) and progression free survival (PFS) from the time of gefetinib resistance in the subsequent chemotherapy group (13.9 m and 5.2 m, respectively) were longer than the local therapy group (7.1 m and 3.1 m, respectively) and the BSC group (3.7 m and 1.1 m, respectively; P < .01). Furthermore, we found that patients who accepted subsequent therapy and continued gefitinib at the same time got better PFS and OS. Local therapy and in combination with continuation of gefitinib treatment could prolong time from local progress to distant metastasis. Conclusions: Subsequent therapy, especially sequential chemotherapy and gefitinib could bring gefetinib resistance NSCLC better survival outcome. Local therapy could also be a reasonable choice for local progress or metastasis patients during gefitinib treatment.

Tyrosine kinase inhibitors (TKI) treatment of non-small cell lung cancer (NSCLC) patients (p) based on EGFR mutations (m) status in serum only.
Subcategory:
Metastatic Non-small Cell Lung Cancer
Category:
Lung Cancer - Non-small Cell Metastatic
Meeting:
2013 ASCO Annual Meeting
Session Type and Session Title:
This abstract will not be presented at the 2013 ASCO Annual Meeting but has been published in conjunction with the meeting.
Abstract Number:
e19088

Citation:
J Clin Oncol 31, 2013 (suppl; abstr e19088)

Author(s):
Laia Capdevila, Enric Carcereny, Itziar de Aguirre, Sara Cros, Cristina Queralt, Teresa Moran, Cristina Buges, Erika Mijangos, Nuria Pardo, Rafael Rosell; Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain; Medical Oncology, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain; Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Barcelona, Spain; Hospital General de Granollers, Granollers, Spain



Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).

Abstract Disclosures

Abstract:


Background: Treatment of EGFR mutated NSCLC p with EGFR TKIs in phase III trials has shown improved efficacy to standard chemotherapy. However, it can be difficult to obtain sufficient tumor tissue for analysis of EGFR m status in a large proportion of p. Nevertheless, so far, no data exists for NSCLC p treated according to EGFR m status in serum alone. Methods: We reviewed our database to identify EGFR mutated p, excluding those for whom status was available in both serum and tissue. We analyzed p treated with an EGFR TKI for whom EGFR m status was known in serum only (status in tissue unknown due to insufficient material). At the same time, we reviewed p in whom EGFR m status in tissue was available over the same period in order to compare clinical characteristics and efficacy parameters: PFS, ORR and overall survival (OS). EGFR m analysis was performed in cell free circulating DNA (cfDNA)isolated from serum and plasma using the QIAmp DNA blood mini kit. Results: 9 p with EGFR m detected in serum and 33 p with EGFR m in tissue were included. In EGFR mutated p in serum, median age 63; male 55.6%; non-smokers 33.3%; former smokers 44.4%; ECOG PS 0-1 66.7%; adenocarcinoma 77.8%; deletion19 33.3%, L858R 66.7%; EGFR TKI treatment in 1st line 44.4%; 2nd or 3rd line 55.6%. ORR: complete response (CR) 22.2%; partial response (PR) 22.2%; stable disease (SD) 22.2%; progressive disease (PD) 11.1%. 2p had poor PS and died prior to evaluation. mPFS 4.7 months (mo). mOS 18 mo. In p with EGFR m in tissue, median age 61; male 36.4%; non-smokers 75.8%; former smokers 24.2%; adenocarcinoma 87.9%; deletion19 75.8%; L858R 24.2%; 1st line 54.5%; 2nd or 3rd line 45.5%. ORR: CR 15.2%; PR 57.6%; SD 12.1%; PD 15.2%. mPFS 8.9 mo. mOS 32.7 mo. The multivariate analysis for OS considering EGFR m in serum differed according to PS (PS 0-1 16.6 mo vs PS > 2 5.2 mo). Conclusions: Obtaining sufficient tissue from NSCLC p for analysis of EGFR m status and other molecular alterations can be difficult. Determination of EGFR m in serum alone is feasible, yields similar results to mutation status in tissue, and could permit us to take treatment decisions.

Non-invasive and quantitative analysis for EGFR T790M mutation in the patients with advanced non-small cell lung cancer received EGFR-TKI therapy.
Subcategory:
Metastatic Non-small Cell Lung Cancer
Category:
Lung Cancer - Non-small Cell Metastatic
Meeting:
2013 ASCO Annual Meeting
Session Type and Session Title:
This abstract will not be presented at the 2013 ASCO Annual Meeting but has been published in conjunction with the meeting.
Abstract Number:
e19101

Citation:
J Clin Oncol 31, 2013 (suppl; abstr e19101)

Author(s):
Rui Chen, Tongtong An, Jie Wang, Hua Bai, Zhijie Wang, Jun Zhao, Meina Wu, Minglei Zhuo, Jianchun Duan, Yuyan Wang, Shuhang Wang; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Cancer Hospital, Beijing, China; Peking University Cancer Hospital, Peking University School of Oncology, Beijing Cancer Hospital, Beijing, China; Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing, China



Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).

Abstract Disclosures

Abstract:


Background: Approximately 50% of advanced non-small cell lung cancer (A-NSCLC) patients with EGFR sensitive mutation who develop acquired resistance to EGFR-TKIs reportedly have a secondary EGFR T790M mutation. Establishing a dynamical, quantitative and noninvasive detection system of EGFR T790M mutation in process of disease therapy for NSCLC is critical to personalized targeted therapy. Methods: 135 A-NSCLC patients with EGFR mutation who received EGFR-TKIs and presented acquired resistance (PFS≥6 months) were included into this study. All patients provided the plasma samples for molecular analysis when disease progressed. 109 patients of them had matched TKI-naive plasma. T790M mutation was measured qualitatively and quantitatively by ARMS and Digital PCR (DggPCR), respectively. Association of T790M mutation with clinical charateristics were evaluated. Results: DgPCR was more sensitive than ARMs to detect T790M mutation in plasma [pre-treatment 29.4% (32/109) VS 5.5% (6/109); post-treatment: 43.0% (58/135) VS 25.2% (34/135)]. 32 patients with pre-treatment T790M mutation predicted shorter PFS and OS compared with 77 T790 M negative patients (PFS, F 12.7 VS 9.2 months, P=0.004, GOS, F 27.0 VS 18.8 months, P=0.002). Patients with or without post-treatment T790M mutation have no significantly different PFS and OS. However, quantified the ratio of copy number of mutant T790M to wild-type by DgPCR, patients were divided into high-frequency groups (≥5%), low-frequency group (0%-5%) and wild-group (0%) according to the number of positive signals observed from DgPCR results. 12 patients in high-frequency group showed shorter PFS and OS compared with wild group and low-frequency group (PFS 9.5 VS 11.9 months, P=0.033, G9.5 VS 13.6 months, P=0.028, GOS, F 18.5 VS 21.2 months, P=0.044, 18.5 VS 28.8 months, P=0.001). Conclusions: Non-invisive and quantitative detection of T790m mutation by digital PCR is feasible in clinical practice. High contents of T790M when disease progression after EGFR-TKIs therapy predicted poor prognosis.

Treatment of advanced recurrent NSCLC with daily oral vinorelbine: A phase I trial.
Subcategory:
Metastatic Non-small Cell Lung Cancer
Category:
Lung Cancer - Non-small Cell Metastatic
Meeting:
2013 ASCO Annual Meeting
Session Type and Session Title:
This abstract will not be presented at the 2013 ASCO Annual Meeting but has been published in conjunction with the meeting.
Abstract Number:
e19108

Citation:
J Clin Oncol 31, 2013 (suppl; abstr e19108)

Author(s):
Amanda Tufman, Astrid Borgmeier, Sylvia Guetz, Joachim Von Pawel, Achim Rittmeyer, Rudolf M. Huber; Ludwig Maximilians University of Munich, Munich, Germany; Ludwig-Maximilians-University of Munich, Munich, Germany; Robert-Koch Clinic Leipzig, Leipzig, Germany; Pneumology Clinic, Asklepios Fachkliniken Gauting, Munich, Germany; Lungenfachklinik Immenhausen, Immenhausen, Germany



Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).

Abstract Disclosures

Abstract:


Background: Metronomic regimens, in which small, frequent doses of chemotherapy are administered, have been suggested to lower toxicities while maintaining, or even improving, efficacy. The high frequency of administration aims to expose the tumor continuously to the drug, thereby preventing the recovery of malignant cells between cycles. Previous studies have shown that the administration of oral vinorelbine thrice weekly is feasible and well tolerated. We present a phase I dose finding study in which a regimen of daily oral vinorelbine was evaluated in pretreated patients with advanced NSCLC. Methods: Pretreated patients with advanced NSCLC were treated with vinorelbine (Navelbine oral) at fixed daily doses of 20 mg, 30 mg, 40 mg or 50 mg for 21 days of each four-week cycle. The primary end point was the identification of the maximum tolerated dose, which was reached when two out of six patients experienced dose limiting toxicity (DLT) in cycle 1 or 2. Results: 27 patients with advanced NSCLC (78% stage IV, median age 65 y) were enrolled. Most (93%) had received previous systemic therapy (mean: 2.6 lines). Daily administration of oral vinorelbine was well tolerated up to 30 mg/d without any DLT. At 40 mg one of three patients experienced DLT in cycle 1 and another patient in cycle 2. Three out of six patients had DLT at the dose level of 50 mg. Therefore, the recommended dose was established at 30 mg/d in cycle 1, with escalation to 40 mg/d in cycle 2 if no DLT had occurred. Eleven patients (2 out of 7 treated with the recommended dose) experienced treatment-related toxicities of grade 3 or higher. The adverse events were primarily hematological (febrile neutropenia: 14.8%, leukopenia: 29.6%, lymphopenia: 18.5%, neutropenia: 18.5%). One patient died as a result of colitis. The frequency of non-hematological toxicities of grade 3 or higher was low with only single cases reported for nausea, fatigue, neutropenic sepsis, pneumonia, increased gamma-glutamyltransferase and anorexia. Conclusions: Daily administration of oral vinorelbine in pretreated patients is feasible and safe. An initial dose of 30mg/d is well tolerated and can be increased to 40mg/d in cycle 2. Further studies are warranted to evaluate the efficacy and safety of this novel approach. Clinical trial information: EudraCT number 2006-001573-25.

Clinical benefit of second EGFR-TKI retreatment on overall survival in patients with advanced non-small-cell lung cancer harboring EGFR-mutation positive after failure of the initial EGFR-TKI treatment: A retrospective analysis.
Subcategory:
Metastatic Non-small Cell Lung Cancer
Category:
Lung Cancer - Non-small Cell Metastatic
Meeting:
2013 ASCO Annual Meeting
Session Type and Session Title:
This abstract will not be presented at the 2013 ASCO Annual Meeting but has been published in conjunction with the meeting.
Abstract Number:
e19164

Citation:
J Clin Oncol 31, 2013 (suppl; abstr e19164)

Author(s):
Masanao Nakashima, Takashi Hirose, Yasunari Oki, Yasunori Murata, Tomohide Sugiyama, Hiroo Ishida, Kentaro Okuda, Toshimitsu Yamaoka, Tohru Ohmori, Tsukasa Ohnishi; Showa University School of Medicine, Tokyo, Japan; The Division of Respiratory and Allergy of Internal Medicine, Showa University School of Medicine, Tokyo, Japan



Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).

Abstract Disclosures

Abstract:


Background: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) bring the best result to EGFR-mutation positive non-small cell lung cancer patients, but most lead to drug resistance. These acquired resistances are associated with T790M mutation or Met amplification, HGF expression. To assess whether affects overall survival in these patients, we did a retrospective study comparing survival outcomes in 2nd EGFR-TKI treated patients with controls without 2nd EGFR-TKI screened during the same time period. Methods: We examined overall survival in thirty-two of 52 patients with advanced, EGFR-mutation-positive NSCLC who treated 1st EGFR-TKI (gefitinib) from January 2009 to December 2012. We identified 16 patients who were given 2nd EGFR-TKI (erlotinib) after failure of the initial gefitinib treatment (retreatment group) with 16 patients who were not given 2nd EGFR-TKI but given only chemotherapy (control group), 20 patients who might treat with 2nd EGFR-TKI or chemotherapy at that time were excluded in progress after failure of the initial gefitinib treatment. To assess differences in overall survival, we assessed subsets of clinically comparable 2nd EGFR-TKI retreatment group. Results: Among 16 patients who were given 2nd EGFR-TKI, retreatment group who were given one or two cytotoxic chemotherapy from 1st EGFR-TKI to 2nd EGFR-TKI, median overall survival from initiation of the diagnosis with advanced IIIB/IV stage or surgical recurrent NSCLC was 24.2 months. 16 patients of control group who were given from second to seven line cytotoxic chemotherapy, overall survival was 15.8 months (p=0.021). Retreatment group who were given 2nd EGFR-TKI was significantly longer than control group in EGFR mutation positive patients. Response rate and disease control rate with 2nd EGFR-TKI retreatment are 12.5% and 31.3%. Conclusions: In patients with advanced, EGFR mutation positive NSCLC, retreatment group who were given 2nd EGFR-TKI therapy was associated with improved survival compared with control group who were given only cytotoxic chemotherapy.

Response to erlotinib and prognosis for patients with de novo epidermal growth factor receptor (EGFR) T790M mutations.
Subcategory:
Metastatic Non-small Cell Lung Cancer
Category:
Lung Cancer - Non-small Cell Metastatic
Meeting:
2013 ASCO Annual Meeting
Session Type and Session Title:
Poster Discussion Session, Lung Cancer - Non-small Cell Metastatic
Abstract Number:
8018

Citation:
J Clin Oncol 31, 2013 (suppl; abstr 8018)

Author(s):
Gregory J. Riely, Helena Alexandra Yu, Maria E. Arcila, Matthew David Hellmann, Marc Ladanyi, Mark G. Kris; Memorial Sloan-Kettering Cancer Center, New York, NY



Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).

Abstract Disclosures

Abstract:


Background: A secondary mutation in exon 20 of EGFR, T790M, is the most common cause of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in patients with EGFR mutant lung cancers. De novo EGFR T790M mutations in TKI-na&iuml;ve patients are rare when assessed by standard genotyping methods. The response to EGFR TKIs in patients with de novo EGFR T790M mutations is unknown. Methods: Patients with EGFRmutations were identified through routine testing, using PCR-based fragment length analysis, mass spectrometry-based genotyping (Sequenom), and Sanger sequencing. Clinical characteristics, progression free survival (PFS) from start of EGFR TKI and overall survival (OS) were obtained from the medical record. Results: From 2008-2012, we observed EGFR T790M in 21 tumors from 20 patients who had not previously been treated with an EGFR TKI representing <2% of all tumors with identified EGFR mutations. Two patients are included in reports from the Lung Cancer Mutation Consortium. The median age at lung cancer diagnosis was 57 (range 35-90). 55% presented with stage IV disease. 60% were women. 65% were never-smokers. In all cases, T790M occurred concurrently with another EGFR mutation, L858R (76%, 16/21) or exon 19 deletion (24%, 5/21). Compared to a contemporary cohort of 593 patients with EGFR mutations, in these patients with de novo EGFR T790M, L858R was more frequent than exon 19 deletion (p=0.003). Thirteen patients received erlotinib monotherapy as treatment for metastatic disease. Their response rate (CR+PR) was 9% (1/11, 95% Confidence Interval: 0-40%). SD was observed in 36% (4/11). The median progression-free survival was 3 months and the median overall survival was 16 months. Conclusions: De novo EGFR T790M mutations are rare and occur most commonly with EGFR L858R. Overall survival for patients with de novo EGFR T790 mutations is shorter than what is seen in patients with EGFR exon 19 deletions or L858R, and appears more similar to EGFR wild-type patients. Response rate to EGFR TKI in these patients is low. EGFR TKI therapy for patients with de novo EGFR T790M appears to have limited objective benefit and should be considered only after standard cytotoxic chemotherapy.