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R. Perez-Soler
Moderator of
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MO06 - NSCLC - Chemotherapy I (ID 108)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Medical Oncology
- Presentations: 14
- Moderators:R. Perez-Soler, P.M. Ellis
- Coordinates: 10/28/2013, 16:15 - 17:45, Parkside Ballroom A, Level 1
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- Abstract
- Presentation
Background
It is reported that epidermal growth factor receptor (EGFR) mutation is frequent in non-small cell lung cancer (NSCLC) patients who are presenting with miliary intrapulmonary carcinomatosis. We often encountered disseminated carcinomatosis as well as intrapulmonary carcinomatosis. This study aims to investigate the clinical characteristics of patients with miliary intrapulmonary or disseminated carcinomatosis.Methods
Patients with advanced NSCLC who harbor EGFR mutation and presented with miliary intrapulmonary or disseminated carcinomatosis were enrolled respectively, from September 2005 to January 2011. EGFR mutations in exons 18-21 were confirmed by pyroseqeuncing method after genomic DNA was extracted from paraffin-embedded tissue specimens. Clinical characteristics, responses to treatment and outcome were collected from medical records.Results
Histology of sixty-four patients with NSCLC who have EGFR mutation revealed adenocarcinoma. The most frequent mutation was in-frame deletions in exon 19 (n=44, 68.7%). An arginine-for-leucine substitution at amino acid 858 (L858R) and point mutation in exon 18 (G719A) were detected in 19 (29.7%) and 1 (1.7%) patient, respectively. Patients with miliary intrapulmonary or disseminated carcinomatosis were more common in female (80.0% vs. 55.1%, p=0.084), non smoker (80.0% vs. 53.1%, p=0.063), and in-frame deletions at exon 19 (86.7% vs. 63.3%, p=0.087), however there were no significant difference statistically. They showed relatively shorter progression free survival (PFS) to EGFR tyrosine kinase inhibitors (median PFS 9.7 vs, 12.8 months, p=0.003) and poorer overall survival (median OS 15.9 vs. 29.0 months, p=0.077) compared to patients without miliary metastasis. In multivariate analysis, higher metabolic tumor volume (MTV) in PET-CT was confirmed to be an independent predictor of shorter overall survival, when considered together with tumor stage, gender and smoking status (hazard ratio for MTV: 1.001; p = 0.027).Conclusion
The data indicate that NSCLC presenting miliary intrapulmonary or disseminated carcinomatosis were more common in female, adenocarcinoma, non smoker and in-frame deletions in exon 19 was comparatively frequently detected in those patients, however there were no statistically significant difference. PFS to EGFR tyrosine kinase inhibitors was less in patients with miliary intrapulmonary or disseminated carcinomatosis and overall survival was poorer compared to patients without miliary metastasis. Poor clinical course of these patients might be associated with high tumor burden represented by metabolic tumor volume or total lesion glycolysis.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO06.02 - Monitoring EGFR T790M with plasma DNA in lung cancer patients treated with EGFR tyrosine kinase inhibitor in prospective observational study (ID 1399)
16:15 - 17:45 | Author(s): K. Aoe, N. Sueoka-Aragane, N. Katakami, M. Satouchi, S. Yokota, K. Iwanaga, S. Kimura, S. Negoro
- Abstract
- Presentation
Background
Detection of mutations with plasma DNA isolated from peripheral blood is an alternative method of biopsy. The gatekeeper T790M mutation of EGFR has been observed in half of patients who acquired resistance to EGFR tyrosine kinase inhibitor (EGFR-TKI). Considering that majority of lung cancer recurrence occurs as distant metastases, determination of T790M using a non-invasive mutation detection system with plasma DNA would be useful. We recently developed a novel non-invasive, fully-automated monitoring system, MBP-QP (mutation-biased PCR and quenching probe) method, to detect T790M using plasma DNA. The detection limit was two copies of control plasmid and 0.2 ng of genomic DNA, the T790M mutation was detected in plasma DNA from 53% of lung adenocarcinoma patients who acquired resistance in the previous retrospective study. Compared with the other methods such as PNA-LNA PCR clamp, the cycleave PCR technique, and digital PCR, the MBP-QP method is simple, sensitive, and reflective of clinical course. To determine the usefulness of the MBP-QP method for monitoring T790M during treatment of EGFR-TKI, a prospective clinical study has been performed.Methods
This is a prospective, multicenter observational study involving lung adenocarcinoma patients carrying EGFR activating mutations such as L858R and exon 19 deletions treated with EGFR-TKI. Primary objective was to determine whether T790M was detected with plasma DNA at the time point of progressive disease (PD), and the secondary objective was correspondence of T790M with plasma and cancer specimens. The association between detection of T790M and effect of EGFR-TKI were also investigated as the exploratory objective. Plasma DNA was isolated from the patients before treatment of EGFR-TKI, every four months during treatment, at the time of occurrence of PD, and after two courses of post-chemotherapy.Results
Ninety lung adenocarcinoma patients treated with EGFR-TKI were enrolled, in whom 51% of L858R and 49% of exon 19 deletions were determined in tumor specimens before treatment. Most of the patients, 92.1%, had adenocarcinoma. 62% (55/90) was stage IV, and 29% (26/90) had postoperative recurrent disease. 43% (38/90) of the patients were treated with EGFR-TKI as the first-line therapy, and the rest of them were previously treated including 17% of the patients experienced with EGFR-TKI. T790M was detected in 23% (21/90) among the entire patients. Forty patients showed PD two years after beginning of this trial, and T790M was detected in 13 patients among the patients who acquired resistance to EGFR-TKI; the frquency of T790M positive among the patients with PD was 32.5% (13/40). Although T790M was temporarily detected during treatment of EGFR-TKI in 8 patients who were still responded to EGFR-TKI, is disappeared after that.Conclusion
T790M was detected in plasma DNA isolated from lung cancer patients whose diseases were progressed. Continuous detection of T790M in plasma DNA seemed to be related with occurrence of PD.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO06.03 - Bevacizumab and erlotinib or bevacizumab, cisplatin and pemetrexed in patients with metastatic non-small cell lung cancer: EGFR mutation based treatment allocation and repeat biopsy at progression in the SAKK19/09 (BIOPRO) trial (ID 1862)
16:15 - 17:45 | Author(s): O. Gautschi, N. Mach, L. Bubendorf, Q. Li, A. Zippelius, R. Stahel, R. Cathomas, M. Fruh, D. Betticher, S. Peters, D. Rauch, M. Brutsche, S. Savic, R. Jaggi, S. Rothschild, E. Oppliger Leibundgut, C. Pilop, L. Stalder, M. Pless, A. Ochsenbein
- Abstract
- Presentation
Background
Treatment allocation by EGFR mutation and maintenance therapy are two new standards for patients (pts) with metastatic non-small cell lung cancer (NSCLC). This multicenter phase II trial (NCT01116219) for the first time prospectively tested pemetrexed and bevacizumab maintenance therapy in pts with EGFR wild type NSCLC, and included repeat biopsy at progression to study molecular mechanisms of drug resistance. Pts with EGFR mutation were treated with erlotinib and bevacizumab, based on the results of the previous SAKK19/05 trial.Methods
100 pts were enrolled with metastatic nonsquamous NSCLC, sufficient material for mutation analysis and translational research, and consent to repeat biopsy at progression. Pts with EGFR wild type received 4 cycles of bevacizumab 7.5mg/kg, cisplatin 75mg/m2 (or carboplatin AUC5) and pemetrexed 500mg/m2 every 3 weeks, followed by maintenance therapy with bevacizumab and pemetrexed until progression. Pts with EGFR mutation received bevacizumab 7.5 mg/kg every 3 weeks and erlotinib 150 mg daily until progression. Pts were followed by CT-scan every 6 weeks and repeat biopsy was performed at progression. The primary endpoint was progression free survival (PFS) at 6 months. For an unpromising PFS at 6 months rate of ≤20% and a promising rate of ≥35%, 77 patients with EGFR wild type were needed to reach a power of 90% and an alpha level of 5%. Secondary endpoints were median PFS, overall survival (OS), best response rate of CR+PR (RECIST), and further biomarkers including KRAS, thymidylate synthase (TS), and multigene expression.Results
Seventy-seven pts with EGFR wild type and 20 pts with EGFR mutation were evaluable, 3 pts were not evaluable. Pts on bevacizumab and chemotherapy received on average 9 cycles (range 1-25). No unexpected toxicities were observed. PFS at 6 months was 45.5% (CI: 34.1%, 57.2%), median PFS was 6.9 (CI: 4.6, 8.3) months, OS was 12.1 (CI: 8.7, 14.7) months, and best response rate of CR+PR was 62%. Sixteen pts remain on treatment. Repeat biopsy at progression was successful in 31 of 39 (79%) of patients on trial treatment, and except for one transient pneumothorax, no relevant complications occurred. KRAS mutation was associated with poor overall survival (HR 2.0, CI: 1.05, 3.88; P=0.03), but not with PFS or best response. Pts on bevacizumab and erlotinib received on average 16 cycles (range 6-37). PFS at 6 months was 70.0% (CI: 45.7%, 88.1%), median PFS was 14.0 (CI: 8.8, NA) months, median OS is not yet reached, best response rate of CR+PR was 70%, 11 pts remain on treatment. Further analysis of serial serum and tumor samples is ongoing.Conclusion
Compared with the previous POINTBREAK trial of pemetrexed and bevacizumab maintenance in genetically unselected pts, this trial demonstrates almost identical survival rates in pts with EGFR wild type. KRAS mutation was prognostic, repeat biopsy at progression was feasible, and laboratory analysis is ongoing to validate TS and to develop a predictive gene signature. Firstline therapy with erlotinib and bevacizumab is promising in pts with EGFR mutation, and this combination is further tested in the ongoing ETOP 2-11 BELIEF trial.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO06.04 - A Randomized Phase 3 Study Comparing First-line Pemetrexed plus Cisplatin Followed by Gefitinib as Maintenance with Gefitinib Monotherapy in East Asian Patients with Locally Advanced or Metastatic Nonsquamous Non-Small Cell Lung Cancer (nSqNSCLC) (ID 1943)
16:15 - 17:45 | Author(s): J.C. Yang, K. Park, T.S.K. Mok, J.H. Kang, V. Srimuninnimit, C. Lin, D. Kim, C. Tsai, H. Barraclough, S. Altug, M. Orlando
- Abstract
- Presentation
Background
The IPASS study reported that in a clinically selected lung cancer patient population (East Asian, light ex-/nonsmokers with adenocarcinoma) gefitinib (G) provided superior progression-free survival (PFS) than chemotherapy with carboplatin/paclitaxel; however, the benefit was restricted to patients with epidermal growth factor receptor gene (EGFR)-mutant tumors whereas patients with wild-type (WT) tumors had inferior outcomes. Pemetrexed, in combination with cisplatin, (PC) has demonstrated improved efficacy in first-line treatment of nSqNSCLC and is a preferred chemotherapy choice. The primary objective was to compare PC induction therapy followed by G as maintenance therapy to G monotherapy, in terms of PFS, as first-line treatment in a similar “IPASS” patient population.Methods
Patients with unknown EGFR mutation status (N=236) were randomized 1:1 to PCG treatment for 6 cycles or G. Patients on Arm A without progressive disease after 6 cycles received G maintenance therapy. Stage IIIB/IV nSQ NSCLC, light ex-smokers or never-smokers, and ECOG PS 0-1 patients with no prior systemic therapy were eligible. Primary endpoint analysis was conducted using a Wilcoxon test after 169 PFS events. This assessment provided 80% power if the true hazard ratio (HR) was 0.65. Tissue samples from consenting patients were analyzed for EGFR mutation status.Results
Baseline characteristics were balanced across treatment arms. One-hundred-forty-one patients provided tissue for EGFR mutation analysis (59.7%). Mutation status was determined for 74 samples (52.5%);50/74 samples (67.6%) had mutations (mutation type: EX19_DEL, n=25; L858R, n=23; other, n=2). The primary analysis of PFS showed no significant difference between treatment arms (Wilcoxon p=0.217). The unadjusted HR was 0.85 (95% CI: 0.63, 1.13). During most of the study period, the KM curve for PC remained above the G curve. In a prespecified subgroup analysis, EGFR-by-treatment interaction was statistically significant (p=0.008), showing treatment effect significantly differed by EGFR mutation status. The HR for PFS favored PC in both EGFR-mutated and EGFR-WT patients, but the magnitude of benefit was greater in EGFR-WT patients [EGFR-mutated patients HR=0.83 ([95% CI: 0.42, 1.62], p=0.585); EGFR-WT HR 0.18 ([95% CI: 0.06, 0.51], p=0.001)]. HRs for ITT and EGFR-mutated patients should be interpreted with caution as they were not constant. Arm A had more patients with ≥1 possibly drug-related CTCAE grade 3/4 TEAEs but similar rates of all-grade TEAEs during induction. Selected grade 3/4 or all-grade TEAEs which occurred significantly more included anemia, neutropenia, emesis, and neuropathy in Arm A and AST/ALT elevations, diarrhea, pruritus, and skin rash in Arm B. The toxicity profile was similar in both arms during the G maintenance period.Conclusion
In the ITT population, the PFS difference was not statistically significant. In the biomarker assessable population, results are consistent with the existing consensus that patients with WT EGFR do not benefit with front-line EGFR TKI treatment. Overall, the results show that identification of the EGFR mutational status is key in the management of advanced NSCLC. Even in the presence of clinically favorable predictors of EGFR mutation positivity (>60% in our population), “empirical” choice of EGFR TKIs as front-line therapy may be detrimental to NSCLC patients without EGFR mutations.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO06.05 - DISCUSSANT (ID 3937)
16:15 - 17:45 | Author(s): P.L. Mitchell
- Abstract
- Presentation
Abstract not provided
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MO06.06 - Oral vinorelbine (NVBo) and cisplatin (P) or pemetrexed (Pem) and P as first-line chemotherapy for non squamous (NS) metastatic or locally advanced non small cell lung cancer (M or LA NSCLC): Final results of a prospective randomised phase II trial (NAVoTrial 1) (ID 276)
16:15 - 17:45 | Author(s): E. Tan, M. Krzakowski, J. Kollmeier, R. Gervais, E. Dansin, M. Serke, A. Favaretto, L. Havel, M. Cobo, A. Szczesna, L. Ciuffreda, J. Jassem, M. Nicolini, R. Ramlau, D. Amoroso, B. Melotti, M.T. Almodovar, N. Vaissière, M. Riggi, J. Bennouna
- Abstract
- Presentation
Background
NVBo and P are an established regimen in advanced NSCLC. The approval of Pem and P in NS NSCLC recognises histology as treatment driver even if the higher chemosensitivity of NS NSCLC is recognised and reported with other chemotherapies (Ardizzoni. JNCI 2007). NVBo + P also showed better survival in NS NSCLC than in Squamous NSCLC (Tan. Ann.Oncol. 2009). The current randomised (2:1) phase II trial assessed disease control (DCR) (SD + PR + CR) of NVBo/CDDP or PEM/CDDP in NS NSCLC.Methods
Stage IIIB/IV untreated/relapsed NS NSCLC pts were randomised to receive q3w NVBo 80 mg/m² D1D8 (60 at Cycle 1) + P 80 mg/m² D1 (Arm A) or Pem 500 mg/m² + P 75 mg/m² D1 (Arm B). After 4 cycles of combination, non PD pts received single agent NVBo (Arm A) or PEM (Arm B) as maintenance until progression or toxicity. Pts were randomised on a 2/1 basis and stratified according to Stage (IIIB - IV - relapse), non SCC confirmed by histology or cytology, gender, smoking status and centre.Results
From 11/09 to 02/11, 153 patients were enrolled in 31 centers and randomised to Arm A (102 pts) or Arm B (51 pts). DCR after combination and maintenance was 75.0% (95% CI, 65.3 to 83.1) in Arm A and 76.5% (95% CI, 62.5 to 87.2) in Arm B. Median PFS was 4.2 (95% CI, 3.6 to 4.7) and 4.3 months (95% CI, 3.8 to 5.6) in Arm A and Arm B, respectively. Median OS was 10.2 months (95% CI, 7.8 to 11.9) and 10.8 months (95% CI, 7.0 to16.4) in Arm A and Arm B, respectively. During the combination period Grade 3/4 neutropenia was 44.0% in Arm A and 18.3% in Arm B but febrile neutropenia was 2% in both arms; grade 3/4 thrombopenia was 0% and 6% in Arm A and Arm B, respectively.Conclusion
Both doublets reported good efficacy and acceptable tolerability. The maintenance allowed continuation of effective treatment with either oral vinorelbine or pemetrexed as single agent, with an acceptable safety with both agents. These results are sufficiently compelling to consider whether a phase III randomised non inferiority study with oral vinorelbine maintenance after induction vinorelbine/cddp could be as effective as pemetrexed maintenance. An oral maintenance may be a definite advantage over intravenous maintenance.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO06.07 - Daily administration of oral vinorelbine: data from a phase I trial in patients with advanced Non-Small Cell Lung Cancer (NSCLC) (ID 2395)
16:15 - 17:45 | Author(s): A. Tufman, A. Borgmeier, S. Guetz, J. Von Pawel, A. Rittmeyer, R.M. Huber
- Abstract
- Presentation
Background
Metronomic regimens, in which small, frequent doses of chemotherapy are administered, have been suggested to lower treatment-associated toxicities while maintaining, or even improving, efficacy. The high frequency of administration aims to expose tumour cells continuously to the drug, preventing recovery between cycles and possibly improving tumour control. We present the clinical and pharmacokinetic data of a phase I dose finding study in which the maximum tolerated dose (MTD) of daily oral vinorelbine was determined in pretreated patients with advanced NSCLC.Methods
Patients (pts) were treated daily with oral vinorelbine (Navelbine® Oral) at fixed doses of 20 mg/d, 30 mg/d, 40 mg/d or 50 mg/d for 21 days of each four-week cycle. Blood sampling for pharmacokinetic assessment was carried out in the first cycle just before drug intake (trough concentrations) on days 1, 8, 15 and 21 and additionally at 1 h, 3 h and 24 h after drug intake on days 1 and 21.Results
Daily administration of oral vinorelbine was well tolerated up to 30 mg/d without any dose limiting toxicities (DLT). At 40 mg one of three patients experienced DLT in cycle 1 and another patient in cycle 2. The MTD was reached at 50 mg/d when three out of six pts experienced DLT in cycle one. The reported DLTs included febrile and non-febrile neutropenia (6 DLTs) as well as fatigue (1 DLT). One patient had an exceptionally good clinical response with a long-lasting tumour remission. Twenty-one pts were evaluable for pharmacokinetic analysis. Blood concentrations of vinorelbine increased with escalating dose levels. Pts were continuously exposed to the drug over the 21-day treatment period as indicated by measurable trough concentrations on days 8, 15 and 21. A slight accumulation of vinorelbine was observed until day 8 based on residual concentrations (ratio c~24h ~ranged 1.96-2.03 between day 1 and either day 8, 15 or 21). The accumulation had no impact on global exposure at repeated dosing, as only minor differences in blood concentrations were detected between day 1 and day 21 (ratio d21/d1 median AUC~0h-24h~: 0.81, 0.92, 1.07, 0.56 at 20 mg/d, 30 mg/d, 40 mg/d and 50 mg/d, respectively). Data on four pts experiencing DLT were available (1 pt at 40 mg/d, 3 pts at 50 mg/d). Only one DLT correlated with an evidently high 24 h blood exposure to vinorelbine.Conclusion
The recommended dose for daily administration of oral vinorelbine is 30 mg in cycle 1 followed by 40 mg in subsequent cycles in the absence of DLT. Further studies are necessary to determine the clinical impact, and possible anti-angiogenic profile of the daily administration schedule of vinorelbine.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO06.08 - A phase 2 randomized open-label study of ramucirumab (IMC 1121B; RAM) in combination with first-line platinum-based chemotherapy in patients (pts) with recurrent or advanced non-small cell lung cancer (NSCLC): final results from non-squamous (NSQ) pts (NCT01160744) (ID 1471)
16:15 - 17:45 | Author(s): R.C. Doebele, D. Spigel, M. Tehfe, S. Thomas, M. Reck, S. Verma, S. Yurasov, D.R. Camidge, P. Bonomi
- Abstract
- Presentation
Background
Vascular endothelial growth factor (VEGF)-mediated angiogenesis plays an important role in NSCLC pathogenesis. RAM is a human IgG1 monoclonal receptor targeted antibody that inhibits VEGF receptor-2 (VEGFR-2) binding and signaling. This study investigates RAM in combination with first-line platinum-pemetrexed chemotherapy in advanced NSCLC.Methods
Eligible patients had Stage IIIb/IV NSCLC, ECOG PS ≤ 2, and no prior chemotherapy or VEGF/VEGFR therapy for metastatic disease. Non-squamous (NSQ) pts with advanced NSCLC were randomized 1:1 to either Arm A: pemetrexed + carboplatin/cisplatin (PEM + Cb/Cis) followed by PEM maintenance or Arm B: Ramucirumab 10 mg/kg + pemetrexed + carboplatin or cisplatin (RAM + PEM + Cb/Cis), followed by RAM + PEM maintenance once every 3 weeks. Patients received the first-line therapy from 4 to 6 cycles (21-day cycle); patients without evidence of disease progression entered a maintenance phase. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), change in tumor size, duration of response, and safety.Results
From Oct 2010 to 2012, 140 pts were randomized (PEM + Cb/Cis: 71; RAM + PEM + Cb/Cis: 69). Overall, baseline patient characteristics were balanced between arms. The median PFS was 5.6 m PEM + Cb/Cis and 7.2 m for RAM + PEM + Cb/Cis; HR 0.75 (90% CI, 0.55, 1.03; p =0.132). ORR (CR + PR) was 38% for PEM + Cb/Cis and 49.3% including one complete response in the RAM + PEM + Cb/Cis arm (p=0.18). Disease control rate (CR + PR + SD) was 70% PEM + Cb/Cis and 86% for RAM + PEM + Cb/Cis ( p = 0.031). Median OS at the time of final PFS analysis was 10.4 m for PEM + Cb/Cis and 13.9 m for RAM + PEM + Cb/Cis; HR 0.83 (90% CI, 0.56, 1.22; p=0.43). Grade ≥ 3 adverse events (AEs) occurring in >10% of patients on RAM containing arm were: anemia, neutropenia, thrombocytopenia, nausea, fatigue, back pain, and hypertension.Conclusion
While the primary endpoint of significant prolongation of PFS was not met, RAM has evidence of clinical activity in combination with PEM + Cb/Cis in patients with NSQ NSCLC. Addition of RAM to PEM + Cb/Cis did not result in excessive or unexpected toxicity.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO06.09 - DISCUSSANT (ID 3938)
16:15 - 17:45 | Author(s): R. Pirker
- Abstract
- Presentation
Abstract not provided
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MO06.10 - Phase II study of bevacizumab, cisplatin and docetaxel plus maintenance bevacizumab as first line treatment for patients with advanced non-small cell lung cancer (n-Sq NSCLC) combined with exploratory analysis of circulating cells (CEC): Thoracic Oncology Research Group (TORG)1016 (ID 1211)
16:15 - 17:45 | Author(s): K. Katono, T. Kato, N. Masuda, F. Oshita, Y. Hosomi, M. Nishikawa, T. Kaburagi, H. Okamoto, S. Morita, K. Watanabe
- Abstract
- Presentation
Background
Bevacizumab has been shown to amplify efficacy against n-Sq NSCLC in combination with platinum doublet, especially taxane including regimens. Docetaxel is one of best taxane composition combined with cisplatin for first line treatment for NSCLC, and known to have anti-angiogenic effect and may act synergistically with VEGF inhibiting agent. The object of this study was to assess the efficacy and safety of bevacizumab, cisplatin and docetaxel combination treatment in patients with chemonaive n-Sq NSCLC patients. (Trial Registry: UMIN 000004368)Methods
Eligible patients had advanced or recurrent n-Sq NSCLC with no prior chemotherapy. Patients having brain metastasis or history of hemoptysis were ineligible. Patients received 4 cycles of docetaxel (60mg/m[2]), cisplatin (80mg/m[2]) and bevacizumab (15mg/kg) on day1 every 3 weeks followed by Bev alone as maintenance every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was response rate (RR) and planned sample size of this phase II study was 47 patients (Simon's two-stage minimax design). We measured circulating endothelial cells (CEC) count day1 and 8 of first cycle for exploratory analysis of efficacy and safety prediction.Results
From Oct 2010 to Apr 2012, 47 patients (28 males/ 19 females, median age, 61 years, 39-73) were enrolled. Stage IIIB/IV/recurrent: 5/39/3, ECOG PS 0/1: 31/16. All patients were adenocarcinoma, EGFR status: mutated/wild/unknown: 13/31/3. Bevacizumab maintenance were administered in 87% (41/47) of the patients and 9 was median number of delivered course, 4 course of induction and 5 course of maintenance. Dose reduction was required in 28% (13/47) of the patients. Thirty-five partial responses and 11 stable diseases were observed among 47 patients, yielding a RR of 74.5% (95% confidence interval: 59.7-86.1%) and disease control rate of 97.9% (88.7-99.9%), respectively. The median progression free survival duration in the patients was 9.0 (7.0-11.3) months. Grade 3/4 leukopenia, neutropenia, hypertension, nausea and febrile neutropenia were observed in 60, 96, 47, 13 and 9% of the patients, respectively. Alveolar hemorrhage (Grade 5) after 4 cycle occurred in one patient.Conclusion
Bevacizumab, cisplatin and docetaxel combination followed by bevacizumab maintenance treatment was highly effective in patients with n-Sq NSCLC, with acceptable toxicity. Exploratory analysis of CEC is ongoing and will be presented.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO06.11 - A Phase II Trial of Paclitaxel, Pemetrexed and Bevacizumab in Patients with Untreated, Advanced Lung Cancers (ID 3142)
16:15 - 17:45 | Author(s): M.C. Pietanza, M.D. Hellmann, N. Rizvi, C.G. Azzoli, S. Smith-Marrone, J. Fiore, L.B. Tyson, D.K. Sumner, A.B. Hergianto, S.L. Kass, C.P. Miller, C.S. Sima, B. Zhao, M.S. Ginsberg, L.H. Schwartz, M.G. Kris
- Abstract
- Presentation
Background
Standard front-line treatment for patients with unresectable or metastatic non-small cell lung cancer (NSCLC) is a platinum-based doublet with bevacizumab regimen, which achieves objective response rates (ORR) of 35% and median survival of 12 months. However, many patients with lung cancer are not eligible for cisplatin because of baseline neuropathy, hearing loss, renal insufficiency, or comorbid medical conditions. Although carboplatin is often substituted for cisplatin, it also is associated with similar toxicities, albeit with a smaller risk. This phase II trial of paclitaxel, pemetrexed, and bevacizumab was designed to avert the toxicities of platinum-based chemotherapeutic regimens and determine the efficacy of such a "non-platinum" containing doublet with bevacizumab.Methods
Patients with untreated, advanced NSCLCs were enrolled if they had measurable disease (RECIST 1.0) and adequate organ and marrow function. Patients were excluded if they had squamous cell carcinoma; hemoptysis; symptomatic or hemorrhagic brain metastases; history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess; and myocardial infarction or stroke within 6 months prior to enrollment. For six 28-day cycles, patients received: paclitaxel 90 mg/m[2] (days 1, 8, and 15), pemetrexed 500 mg/m[2] (days 1 and 15), and bevacizumab 10 mg/kg (days 1 and 15). Patients with response or stable disease continued pemetrexed and bevacizumab every 14 days until progression or unacceptable toxicity. Patients were evaluated on days 1, 8 and 15 of each 28-day cycle. To assess response, CT scans were performed after cycles 1 and 2, and every 2 cycles thereafter. ORR was the primary endpoint.Results
Forty-four patients were enrolled: 50% women, median age of 59 years (range, 31 to 77), 89% with Karnofsky performance status ≥80%. Mutation status was known in 38 patients (KRAS, n=16; ALK, n=3; BRAF V600E, n =2; Her2 insertion/PIK3CA, n=1; EGFR Exon 20 insertion, n=1; none, n=15). The ORR was 52% (95% CI, 37-68), with 23 partial responses and no complete responses. The median overall survival and progression-free survival were 17 months (95% CI, 12-33) and 8 months (95% CI, 6-12), respectively. Grade 3/4 toxicities included fatigue (33%); elevated liver function tests (15%); leukopenia (9%); hoarseness (7%); nausea (7%); and anemia (7%). Two patients died on study of respiratory failure, possibly related to therapy. No bleeding events were noted.Conclusion
The “non-platinum” containing regimen of paclitaxel, pemetrexed and bevacizumab is an effective first-line treatment for patients with advanced NSCLCs, regardless of mutational status. Long survival was observed, with acceptable toxicities. This regimen warrants further study.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO06.12 - Efficacy and safety of paclitaxel and carboplatin with bevacizumab for the first-line treatment of patients with nonsquamous non-small cell lung cancer (NSCLC): analyses based on age in the phase 3 PointBreak and E4599 trials (ID 2879)
16:15 - 17:45 | Author(s): C.J. Langer, M.A. Socinski, J.D. Patel, A.B. Sandler, J.H. Schiller, L. Leon, S. Hazard, S.S. Ramalingam
- Abstract
- Presentation
Background
A post hoc analysis of NSCLC patients (pts) aged ≥70 y in the pivotal E4599 trial found increased adverse events (AEs) and numerically decreased overall survival (OS) benefit associated with bevacizumab (BEV) compared with pts <70 y. We evaluated the efficacy and safety of BEV by age in pts in a pooled dataset from the E4599 and PointBreak (PB) trials.Methods
Pts randomized to the PC (paclitaxel and carboplatin ) + BEV arms of E4599 and PB received P 200 mg/m[2], C AUC 6, and BEV 15 mg/kg q3w for 6 (E4599) or 4 (PB) cycles; Eligible pts received maintenance BEV alone q3w until disease progression or unacceptable toxicity. OS, progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR), and safety were assessed in pts grouped according to age (<65 y, 65–74 y, 70–74 y, <75 y, and ≥75 y). Pt-level data from the PC + BEV arms of E4599 and PB were pooled and compared with data from pts in the PC-alone arm of E4599.Results
PB and E4599 randomized 467 pts and 434 pts to PC + BEV, respectively, while 444 were randomized to receive PC alone on E4599. Baseline characteristics were balanced between age groups. OS and PFS hazard ratios (HRs) and increases in grade ≥3 AEs for the pooled pt cohort relative to E4599 PC-alone arm are shown (Table). Outcomes were similar in pts <70 y and ≥70 y, and data from the pooled population were similar to those seen in each individual trial (data not shown). ORR for pts <75 y was 39% with PC + BEV vs 26% with PC (P<.01). For pts ≥75 y, ORR was 33% vs 30% (P=.71). DCR in pts <75 y was 70% with PC + BEV vs 53% with PC (P<.01). For pts ≥75 y, DCR was 60% vs 67% (P=.37).Conclusion
In a pooled exploratory analysis of pt data from E4599 and PB, the statistically significant benefit associated with the addition of BEV to PC appeared consistent across all age groups <75y, while pts ≥75 y receiving PC + BEV had no statistically significant survival benefit. Pts receiving PC + BEV had an increase in grade ≥3 AEs compared with pts receiving PC-alone in all age groups.
[a]Relative to PC-alone arm.PB + E4599 <65 y n=735 65–74 y n=453 70–74 y n=203 <75 y n=1188 ≥75 y n=157 HR for OS 95% CI P 0.75 0.62–0.89 <.01 0.80 0.64–1.00 .05 0.68 0.48–0.96 .03 0.78 0.68–0.89 <.01 1.05 0.70–1.57 .83 HR for PFS 95% CI P 0.71 0.60–0.85 <.01 0.62 0.49–0.78 <.01 0.68 0.48–0.96 .03 0.69 0.60–0.79 <.01 0.95 0.62–1.44 .80 E4599 n=499 n=277 n=129 n=776 n=102 Δ Grade ≥3 AEs,[a ]% P 13 <.01 21 <.01 23 <.01 15 <.01 25 <.01 Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO06.13 - BEYOND: a randomized, double-blind, placebo-controlled, multicentre, phase III study of first-line carboplatin/paclitaxel (CP) plus bevacizumab (Bv) or placebo (Pl) in Chinese patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC) (ID 2756)
16:15 - 17:45 | Author(s): C. Zhou, G. Chen, X. Liu, Y. Zhu, S. Lu, J. Feng, J. He, B. Han, J. Wang, G. Jiang, C. Hu, H. Zhang, G. Cheng, X. Song, Y. Lu, H. Pan, W. Zheng, A. Yin, Y. Wu
- Abstract
Background
Bevacizumab, a monoclonal antibody that inhibits angiogenesis via the vascular endothelial growth factor (VEGF) pathway, has proven efficacy in extending overall survival (OS) (Sandler et al, 2006) and progression-free survival (PFS) (Sandler et al, 2006; Reck et al, 2009) when added to platinum-doublet chemotherapy as first-line treatment for advanced non-squamous NSCLC. These pivotal studies included mainly Caucasian patients, however subgroup analyses in Asian patients also reported efficacy of the first-line Bv+CP regimen (Reck et al, 2009). The BEYOND study was initiated to confirm efficacy in a Chinese population.Methods
Patients aged ≥18 years with histologically or cytologically confirmed, locally advanced, metastatic or recurrent advanced non-squamous NSCLC and an ECOG performance status of 0–1 were randomised 1:1 to receive CP (paclitaxel 175mg/m[2] i.v. and carboplatin AUC6 i.v. on day 1 of each 3-week cycle for up to 6 cycles), plus either Pl or Bv 15mg/kg i.v. on day 1 of each cycle, until progression, unacceptable toxicity, withdrawal of patient consent or death. Patients had no prior treatment for advanced NSCLC. Patients were stratified by gender, smoking status and age. The primary endpoint was PFS in the intent-to-treat (ITT) population; secondary endpoints included objective response rate (ORR), OS, exploratory biomarkers and safety. Collection of blood samples for biomarker analyses was mandatory (at baseline, every two cycles during treatment, at progression, and 4–6 weeks post-progression); tissue samples were optional.Results
276 patients were randomised into the study, 138 to each arm. Baseline characteristics were similar in both treatment groups. PFS was prolonged with Bv+CP versus Pl+CP: hazard ratio 0.40 (95% CI 0.29–0.54); median 9.2 versus 6.5 months; p<0.0001 (ITT population). ORR was also improved with the addition of Bv to CP: 54.4% versus 26.3% with Pl+CP. Disease control rate was 94.4% versus 88.7% with Bv+CP and Pl+CP, respectively. Median duration of response was 8.0 months with Bv+CP versus 5.3 months with Pl+CP. OS data are not yet mature. Safety data were similar to previous studies of Bv+CP in NSCLC; no new safety signals were observed. Treatment discontinuation due to adverse events was 18.4% (Bv+CP) and 15.0% (Pl+CP). Treatment-related deaths were low in both arms (Bv+CP: 2.2%; Pl+CP: 0.0%). Detailed safety data and biomarker analyses will be reported.Conclusion
This study confirms that the addition of bevacizumab to first-line platinum-based chemotherapy appears to provide similar PFS benefits in Chinese patients with advanced non-squamous NSCLC compared with global populations. No new safety concerns were reported. -
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MO06.14 - DISCUSSANT (ID 3939)
16:15 - 17:45 | Author(s): W.E.E. Eberhardt
- Abstract
- Presentation
Abstract not provided
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Author of
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MO04 - Lung Cancer Biology I (ID 86)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Biology
- Presentations: 1
- Moderators:G. Sozzi, D.C. Lam
- Coordinates: 10/28/2013, 16:15 - 17:45, Bayside 103, Level 1
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MO04.04 - Aerosol Azacitidine Reduces Methylation Levels of Tumor Suppressor Genes and Prolongs Survival in the Orthotopic Lung Cancer Models in Mice. (ID 1621)
16:15 - 17:45 | Author(s): R. Perez-Soler
- Abstract
- Presentation
Background
Promoter hypermethylation plays an important role in lung cancer carcinogenesis by silencing key tumor suppressor genes (TSG). Reversing the hypermethylation of TSG by direct aerosolized administration of a demethylating agent may have a potential to inhibit lung cancer growth and development. This study examines the therapeutic potential of aerosolized azacytidine (Aza) in the orthotopic mice model of human NSCLC.Methods
Vidaza® (the clinical grade Aza formulation for IV administration) was dissolved into sterile water for injection and aerosolized in a clinical standard aerosol system. The aerodynamic size, the lung deposition, and the Aza level in the lung and circulation of mice were measured by previously described methods. The demethylation and gene reactivation functions of aerosolized Aza were detected by qPCR methylation array and western blotting assay in the human non-small cell lung cancer (NSCLC) tumor tissues from the orthotopic intratracheally inoculated xenograft models in nude mice. The therapeutic efficacy and toxicity of the aerosolized Aza were also evaluated in mice. Mice treated with an intravenously administered Aza with clinically equivalent dose and schedules were used as a comparison.Results
The aerosolized Aza is an appropriate pharmaceutical inhalation formulation with size distribution of about 80% of droplets from 0.1 to 5 micron. This dynamic size range ensures the aerosol droplets depositing in the lower airway as indicated by the recovery of approximately 80% Aza from the lung tissue 20 min after the aerosol administration. In efficacy and toxicity studies, aerosol administration of Aza significantly prolonged the survival of nude mice with intratracheally inoculated human NSCLC tumors. The %-increased in life span was 5- to 10-fold higher than that of a systemic treatment of Aza at a clinically equivalent dose. The aerosolized Aza, at a potentially therapeutic dose, did not cause any detectable lung toxicity or systemic toxicity (myelosuppression). After the aerosolized Aza treatment, the lung tumors were resected and the methylation levels of the 24 promoters driving the lung cancer related tumor suppressor genes (TSGs) in the lung tumors were examined by qPCR methylation array. The aerosolized Aza significantly reduced the methylation level in 9 of the 24 promoters examined. This demethylating effect also resulted in the gene reactivation at the protein level in several tested genes.Conclusion
In our orthotopic NSCLC model, aerosolized Aza was well tolerated with good drug delivery to bronchial epithelium at non-cytotoxic doses. The pharmacodynamic effect of the TSG demethylation and reactivation was observed. Interesting therapeutic efficacy of prolonging survival was observed in our model from aerosolized 5-Aza over intravenous administration in mice. The phase I clinical trial of aerosolized Aza with pharmacodynamic endpoints will be conducted. Acknowledgement: Supported by a NIH (NCI) grant 5R01CA154755-02Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
