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M. Gottfried
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MINI 17 - WT EGFR, Angiogenesis and OMD (ID 131)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 2
- Moderators:R. Feld, R. Dziadziuszko
- Coordinates: 9/08/2015, 16:45 - 18:15, Mile High Ballroom 4a-4f
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MINI17.07 - Efficacy of Nintedanib/Docetaxel after Bevacizumab, Pemetrexed or Taxanes Therapy (ID 1521)
16:45 - 18:15 | Author(s): M. Gottfried
- Abstract
- Presentation
Background:
Nintedanib is a triple angiokinase inhibitor of receptors for vascular endothelial growth factor (VEGF), platelet-derived growth factor and fibroblast growth factor. The randomized, placebo-controlled, Phase III LUME-Lung 1 study (NCT00805194; 1199.13) investigating nintedanib/docetaxel was the first trial of an antiangiogenic agent to demonstrate significant overall survival (OS) benefit in previously treated patients with non-small cell lung cancer (NSCLC) of adenocarcinoma histology; nintedanib/docetaxel is approved in the European Union for the treatment of patients with locally advanced, metastatic or locally recurrent NSCLC of adenocarcinoma histology after 1[st]-line chemotherapy. Here we report LUME-Lung 1 data from the adenocarcinoma population who received 1[st]-line chemotherapy containing bevacizumab, pemetrexed or taxanes.
Methods:
In LUME-Lung 1, 1314 patients with Stage IIIB/IV recurrent NSCLC received either nintedanib/docetaxel or placebo/docetaxel. Primary endpoint was centrally assessed progression-free survival (PFS); OS was a key secondary endpoint. Prior treatment with anti-VEGF agent bevacizumab was a stratification factor. Analyses of the adenocarcinoma population (n=658) according to prior treatment with bevacizumab (n=45 in either arm), pemetrexed (1[st]-line [n=126] or maintenance [n=27]) or taxanes (n=142) were performed to determine if 1[st]-line regimens could influence subsequent outcomes for nintedanib/docetaxel.
Results:
Patient characteristics were generally well-balanced across prior-treatment subgroups. For the adenocarcinoma population, there was no interaction between 1[st]-line treatment with bevacizumab, pemetrexed or taxanes and treatment outcome with nintedanib/docetaxel. Independent of pretreatment, nintedanib/docetaxel-treated adenocarcinoma patients had an OS benefit (Table). In the overall patient population, efficacy outcomes for these subgroups were also similar regardless of prior treatment. Furthermore, there was no significant effect on nintedanib/docetaxel outcomes for the few adenocarcinoma patients who received maintenance pemetrexed. The adverse event (AE) profile for nintedanib/docetaxel in each subgroup was consistent with that reported for the adenocarcinoma population in LUME-Lung 1, with diarrhea and reversible liver enzyme elevations among the more frequently reported AEs. Among patients who received nintedanib/docetaxel, there was no difference between prior-treatment subgroups in the frequency of AEs commonly associated with the prior treatment, such as hypertension with bevacizumab, mucositis with pemetrexed and peripheral neuropathy with taxanes.
Conclusion:
In LUME-Lung 1, regardless of whether a patient with NSCLC of adenocarcinoma histology received 1[st]-line chemotherapy containing bevacizumab, pemetrexed or taxanes, subsequent treatment with nintedanib/docetaxel led to improved OS.Table: OS results in patients with NSCLC of adenocarcinoma tumor histology stratified by ± prior 1st-line bevacizumab, pemetrexed or taxanes treatment
BEV, bevacizumab; CI, confidence interval; HR, hazard ratio; N/D, nintedanib/docetaxel; NSCLC, non-small cell lung cancer; OS, overall survival; PEM, pemetrexed; Pl/D, placebo/docetaxel; TAX, taxanes.No BEV BEV No PEM PEM No TAX TAX N/D Pl/D N/D Pl/D N/D Pl/D N/D Pl/D N/D Pl/D N/D Pl/D Patients, n 298 315 24 21 261 271 61 65 245 271 77 65 Median OS, months 12.6 10.6 14.9 8.7 13.4 10.8 12.0 8.0 12.2 10.3 15.1 11.6 HR (95% CI) 0.85 (0.71–1.01) 0.61 (0.31–1.20) 0.83 (0.68–1.00) 0.79 (0.53–1.18) 0.86 (0.71–1.05) 0.75 (0.51–1.11) Interaction p-value p=0.24 p=0.90 p=0.61
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MINI17.08 - Tumor Growth Over Time with Nintedanib/Docetaxel or Placebo/Docetaxel in Adenocarcinoma NSCLC: Analysis From the LUME-Lung 1 Study (ID 1405)
16:45 - 18:15 | Author(s): M. Gottfried
- Abstract
Background:
Nintedanib (N; Vargatef[®]), a triple angiokinase inhibitor, is approved in the EU in combination with docetaxel (D) for the treatment of patients with advanced NSCLC of adenocarcinoma histology (ACH) after 1[st]-line chemotherapy. In the randomized, placebo-controlled, Phase III LUME-Lung 1 study (NCT00805194; 1199.13), N+D significantly improved overall survival (OS; secondary endpoint) vs D in patients with ACH (median OS: 12.6 vs 10.3 months (m); HR: 0.83 [95% CI: 0.70–0.99]; p=0.0359) and in patients who progressed either during or within 9 m of 1[st]-line therapy (time[T]<9m) (median OS: 10.9 vs 7.9 m; HR: 0.75 [95% CI: 0.60–0.92]; p=0.0073). We explored the impact of on tumor growth over time as a treatment effect of N+D, with a specific focus on early progressors (T<9m) and patients who had progressive disease as best response to 1[st]-line therapy (PD-FLT).
Methods:
Tumor growth was evaluated using all available tumor measurements. Mixed-effects models were used to quantify the non-linear individual relationships between time from randomization and tumor burden, measured as the sum of longest diameter of target lesions (SLD) and assessed by independent central review (RECIST 1.0). Analyses were conducted for the entire population of patients with ACH, T<9m and PD-FLT.
Results:
Estimated mean baseline SLD was 82.5 mm in all patients with ACH, 88.3 mm in T<9m and 98.1 mm in PD-FLT. N+D showed a significant reduction of tumor growth over time (p<0.0001) in patients with ACH compared to D. Treatment difference at 6 months (SLD D group – SLD N+D group) for patients with ACH was 9.7 mm. This treatment difference was even more pronounced in the T<9m group (16.8 mm) and in patients with PD-FLT (19.7 mm). Tumor growth over time for N+D showed a non-linear J-shaped curve, indicating a decline in SLD at the beginning of treatment, which was maintained over time followed by a linear increase (see Figure for curves for the T<9m group). This relationship was consistently observed between populations. For patients treated with D, a linear increase in SLD from baseline over time in all ACH patients, T<9m and PD-FLT was observed. Figure 1
Conclusion:
In the LUME-Lung 1 study, N+D significantly decreased tumor burden and decelerated tumor growth over time compared to D in all patients with ACH and in the groups of patients with the poorest prognosis.
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P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.01-078 - Pembrolizumab vs Platinum-Based Chemotherapy for PD-L1-Strong-Positive NSCLC (ID 2959)
09:30 - 17:00 | Author(s): M. Gottfried
- Abstract
Background:
Platinum-doublet chemotherapy with or without maintenance therapy is the standard-of-care first-line therapy for patients with NSCLC that do not harbor EGFR sensitizing mutations or ALK translocations. Most patients experience disease progression despite treatment with chemotherapy, with median overall survival <12 months. Pembrolizumab (MK-3475), a humanized monoclonal antibody against PD-1, has demonstrated a manageable safety profile and robust antitumor activity as first-line therapy in patients with advanced NSCLC enrolled in the phase 1b KEYNOTE-001 study. Improved efficacy was observed in patients whose tumors strongly expressed PD-L1 (ie, showed membranous staining in ≥50% of tumor cells). The international, open-label, phase 3 KEYNOTE-024 trial (ClinicalTrials.gov identifier NCT02142738) is designed to assess the efficacy and safety of pembrolizumab with those of standard-of-care platinum-doublet chemotherapy in patients with treatment-naive metastatic NSCLC and PD-L1 expression in ≥50% of tumor cells.
Methods:
Patients aged ≥18 years with previously untreated advanced NSCLC without EGFR sensitizing mutations or ALK translocations, membranous PD-L1 expression in ≥50% of tumor cells, Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1, no active autoimmune disease, or history of interstitial lung disease are eligible. PD-L1 expression is determined by immunohistochemistry in newly collected tumor samples at a central laboratory. Patients are randomly assigned in a 1:1 ratio to receive a 200-mg fixed dose of intravenous pembrolizumab every 3 weeks (Q3W) or investigator’s choice of up to 6 cycles of gemcitabine 1250 mg/m[2] plus cisplatin 75 mg/m[2], gemcitabine 1250 mg/m[2] plus carboplatin AUC 5 or 6, pemetrexed 500 mg/m[2] plus carboplatin AUC 5 or 6, pemetrexed 500 mg/m[2] plus cisplatin 75 mg/m[2], or paclitaxel 200 mg/m[2] plus carboplatin AUC 5 or 6; patients with nonsquamous histology may receive pemetrexed 500 mg/m[2] Q3W maintenance therapy. Randomization is stratified by ECOG PS (0 vs 1), histology (squamous vs nonsquamous), and region (East Asia vs non-East Asia). Pembrolizumab will be given for up to 35 cycles or until disease progression, intolerable toxicity, or patient withdrawal. Eligible patients may remain on pembrolizumab therapy after initial radiographic disease progression. Patients who complete 35 cycles of pembrolizumab or who stop treatment after achieving complete response may be eligible for 1 year of pembrolizumab retreatment. Crossover to pembrolizumab is permitted for patients who progress on chemotherapy. Tumor imaging is performed every 9 weeks; response is assessed per RECIST v1.1 by independent central review and by modified RECIST by investigator review. Adverse events will be collected throughout the study and for 30 days (90 days for serious adverse events) thereafter; all toxicities will be graded according to NCI CTCAE v4.0. The primary end point is progression-free survival per RECIST 1.1 by central review; secondary end points are overall response rate per RECIST 1.1, overall survival, and safety. Enrollment is ongoing and will continue until approximately 300 patients are assigned to treatment.
Results:
Not applicable.
Conclusion:
Not applicable.
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-063 - Secretome of BM Mesenchymal Stem Cells: An Emerging Player in NSCLC Progression (ID 190)
09:30 - 17:00 | Author(s): M. Gottfried
- Abstract
Background:
Non-small cell lung cancer (NSCLC) remains the most common cause of cancer-related death worldwide. Patients presenting with advanced stage NSCLC have poor prognosis while metastatic spread accounts for >70% of patients deaths. The major advances in treatment of lung cancer have brought only minor improvements in survival; therefore novel strategic treatment approaches are urgently needed. Accumulating data allocate a central role for the cancer microenvironment including mesenchymal stem cells (MSCs) in acquisition of drug resistance and disease relapse. Several studies that investigate MSCs in the lung cancer microenvironment revealed that they exhibit genetic and functional abnormalities compared to their normal counterparts. Furthermore, studies indicate that translation initiation factors are over expressed in NSCLC and negatively impact its prognosis. Importantly, translation initiation is highly modulated by microenvironmental cues. Therefore, we decided to examine the effect of BM-MSCs from normal donors on NSCLC cell lines with special emphasis on the role of translation initiation in the crosstalk.
Methods:
BM samples were obtained from femur head BM samples of normal donors. NSCLC cell lines (H1299, H460) were treated with BM-MSCs' conditioned medium (i.e secretome) for 72 hours after which NSCLC cells were harvested and assesed for changes in the cells' viability, proliferation/ death, and migration. The cells' were immunoblotted for the levels of translation initiation factors (eIF4E, eIF4GI), their targets, and regulators.
Results:
Our results demonstarted deleterious effects on the cells’ proliferation, viability, death and migration. We also demonstrated reduced levels of translation initiation factors implicated in cancer progression eIF4E and eIF4GI, their targets, and regulators. Finally, we outlined a mechanism by which BM-MSCs' secretome affected NSCLC's MAPK signaling pathway, downredulated the cells' migration and diminshed translation initiation factors' levles.
Conclusion:
Our study investigates the effects of microenvironmental cues on NSCLC cells’ fate and critical translation factors that regulate the cells’ tumorigenesis. We showed that there is direct dialogue between the BM-MSCs’ secretome and NSCLC cells that manipulates translation initiation and critically affects cell fate. We showed inhibitory effect on the lung cancer cells’ migration that is regulated both by MAPK signaling pathways and by translation initiation mechanism. Understanding the molecular events which promote metastasis and improving the means of foretelling their development is a major goal of current clinical research. We suggest that theraputic approach that will sabotage this dialoge, espacially in the BM microenviornment, may diminish lung cancer metastatic spread and morbidity and improve the patients life quality. Figure 1
