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D. Kowalski
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P2.05 - Poster Session with Presenters Present (ID 463)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Radiotherapy
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.05-030 - WBRT Prior EGFR TKIs is Effective Treatment Option for NSCLC Patients with CNS Metastases Harboring EGFR Mutation (ID 5151)
14:30 - 14:30 | Author(s): D. Kowalski
- Abstract
Background:
Central nervous system (CNS) metastases are considered as a common cause of morbidity and mortality in advanced non-small-cell lung cancer (NSCLC). It is estimated that 20–40% of NSCLC develop CNS metastases during their disease course. Sensitivity of chemotherapy is limited in CNS metastases of NSCLC, because of restrict transit function of blood-brain barrier. The main treatment options based on whole brain radiation therapy (WBRT), stereotactic radiosurgery, neurosurgery or combination of them. Median overall survival (mOS) achieved in NSCLC with CNS metastases treated with irradiation methods is 6.5-7.5 months. Introduction of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) – gefitinib, erlotinib, afatinib – improved the treatment possibilities in selected group of NSCLC patients harboring EGFR gene mutations. Also CNS metastatic lesions of NSCLC showed sensitivity to EGFR-TKIs (mOS to 15-17 months). Moreover, concurrent EGFR TKIs and WBRT may be used synergistic because potentially improve survival and delays intracranial progression. The main aim of the study was evaluation weather implementation of WBRT prior EGFR TKIs in NSCLC patients with CNS metastases might influence on their survival in comparison to patients without CNS metastases treated with EGFR TKIs monotherapy.
Methods:
The studied group included 178 NSCLC patients harboring EGFR gene mutation. 160 (110 female, 50 male; median age 67 years) patients with primary NSCLC received EGFR TKIs in first or second line of treatment. 18 patients (16 female, 2 male; median age 69 years), who had diagnosed CNS metastases, received WBRT prior administration of EGFR TKIs.
Results:
The treatment response was showed in both studied group. We did not observed a significant differences in survival in both studied groups. The progression free survival (PFS) in patients with primary NSCLC treated with EGFR TKIs and in patients with CNS lesions treated with WBRT prior EGFR TKIs was 10 vs. 9 months (p=0.785; HR=1.07; 95% CI=0,618-1.866), respectively. Also mOS did not show significance discrepancies in both studied group (26 vs. 32 months, respectively; p=0.32; HR=0.639; 95% CI=0.301-1.356). Implementation of WBRT prior TKIs did not lead to additional neurotoxicity.
Conclusion:
The following study showed that combination of WBRT prior TKIs in NSCLC patients with CNS metastases achieves similar benefit like treatment of primary NSCLC (without CNS metastases) with EGFR TKIs monotherapy. Based on overall data, patients with CNS metastases achieved better response rate when EGFR TKIs are administrated prior WBRT. It may be caused by EGFR TKIs feature which possess CNS penetrability for radiation.
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P2.06 - Poster Session with Presenters Present (ID 467)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.06-006 - Phase I/II Dose Escalation Study of L-DOS47 as a Monotherapy in Non-Squamous Non-Small Cell Lung Cancer Patients (ID 4455)
14:30 - 14:30 | Author(s): D. Kowalski
- Abstract
Background:
L DOS47, a cancer therapeutic designed to exploit the acidic tumour extracellular environment, is a protein conjugate consisting of a urease conjugated to a camelid monoclonal antibody (AFAIKL2) that is targeted to the CEACAM6 antigenic tumour marker. The AFAIKL2 antibody serves as a targeting agent to deliver the enzyme to the tumor sites while the urease enzyme converts urea, an abundant natural metabolite, into ammonia and generates a local pH increase. The combined effect of ammonia toxicity and pH increase is cytotoxic to cancer cells in culture and in xenograft models. This first in human study of L DOS47 was designed to define the maximum tolerated dose of multiple doses of L-DOS47 administered intravenously to patients with non-squamous NSCLC when given as a monotherapy.
Methods:
Stage IIIb or IV histologically confirmed non-squamous NSCLC patients (aged ≥18 yrs, ECOG PS ≤2) receive multiple cycles of L-DOS47 during the study treatment period. L-DOS47 is administered once weekly over 14 days followed by 7 days rest in each treatment cycle. Patients are recruited into cohorts and received the same dose of L-DOS47 on Days 1 and 8 of each treatment cycle. Dose levels of L-DOS47 are escalated in further cohorts following a review of safety data by the Trial Steering Committee.
Results:
Fifty-five (55) pts (median age 61, 53% male) were enrolled in sixteen cohorts (dose levels: 0.12 to 13.55 µg/kg) in four Polish centers. L-DOS47 was well tolerated at the dose levels reviewed. One (1) DLT was reported in a cohort 13 patient (spinal pain). None of the patients treated to date have had a partial or complete response as defined by RECIST v1.1. Thirty-two (32) patients had an overall response of stable disease after completing two cycles of L-DOS47. Thirteen (13) of the 32 patients had a decrease in the sum of diameters of target lesions. One (1) patient in cohort 9 was dosed for 10 cycles without disease progression.
Conclusion:
L-DOS47 monotherapy is well tolerated at dose levels up to 13.55µg/kg.
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P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02b-048 - Oral Vinorelbine Monotherapy in Patients with EGFR+ NSCLC after Failure of EGFR-TKI in First Line: A Prospective Study (ID 4315)
14:30 - 14:30 | Author(s): D. Kowalski
- Abstract
Background:
In advanced/metastatic EGFR+ NSCLC patients (pts) progressing after EGFR-TKIs failure in first line, single-agent chemotherapy (CT) may be offered in pts who are unfit for a platinum combination. In this study (NAVoTRIAL 2), oral vinorelbine (NVBo) was evaluated as monotherapy in advanced NSCLC EGFR+ pts who failed to EGFR-TKIs in first line.
Methods:
Phase II, prospective, multicentre, open-label, international study. Main eligibility criteria: stage IIIB/IV NSCLC, EGFR+, prior EGFR-TKI treatment failure, Karnofsky PS ≥70, no prior CT or immunotherapy. Study treatment until progression or unacceptable toxicity: NVBo 60 mg/m[2] weekly for 3 weeks (first cycle), followed by 80 mg/m[2] weekly for subsequent cycles in absence of grade 3/4 toxicity. The primary endpoint was the disease control rate (DCR = CR + PR + SD, RECIST 1.1).
Results:
Final results: 30 pts included (March 2013 - November 2014). Main pts characteristics: median age: 66.8 years (60% ≥65 years); median Karnofsky PS 90%. Adenocarcinoma 96.7%. ≥3 organs involved (53.3%). All pts harboured EGFR mutation and received prior EGFR-TKI therapy: Gefitinib 73.3%, Erlotinib 16.7%, Afatinib 10%; 33.3% of pts had ≥2 comorbidities; Total number of cycles: 166 (443 doses administered); median number of cycles: 3.5 (range 1-20); median relative dose intensity: 77.6% (range 46.8-105); dose escalation was performed in 76.7 % of pts; Disease control rate 63.3% (95% CI [43.8-80]) and 23.3% of patients with stable disease ≥6 months. Median time to treatment failure: 2.7 months (range 0.4-13.6). Median PFS of 3.3 months (95% CI [1.6-5.4]) and OS of 13.1 months (95% CI [6.1-15.8]). Grade 3/4 toxicities per pt: neutropenia 53.3%, anemia 6.7%, leukopenia 26.7%, fatigue 16.7%, nausea 3.3% and vomiting 6.7%. Three cases of febrile neutropenia reported. No grade 3/4 diarrhoea, constipation, peripheral neuropathies or alopecia.
Conclusion:
NVBo as single-agent CT is a well-tolerated option in advanced EGFR+ NSCLC pts beyond failure of EGFR-TKI in first line. Its favourable tolerability profile allows a prolonged disease control in non-progressing pts.
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PL03 - Presidential Symposium (ID 428)
- Event: WCLC 2016
- Type: Plenary
- Track:
- Presentations: 1
- Moderators:D.P. Carbone, R. Pirker
- Coordinates: 12/06/2016, 08:35 - 10:25, Hall D (Plenary Hall)
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PL03.09 - Phase 3 Study of Ganetespib, a Heat Shock Protein 90 Inhibitor, with Docetaxel versus Docetaxel in Advanced Non-Small Cell Lung Cancer (GALAXY-2) (Abstract under Embargo until December 6, 7:00 CET) (ID 5232)
10:05 - 10:15 | Author(s): D. Kowalski
- Abstract
- Presentation
Background:
Heat shock protein 90 functions as a chaperone to stabilize oncoproteins. Ganetespib (G), a highly potent Hsp90 inhibitor, has demonstrated efficacy in combination with docetaxel (D) over D alone in the second-line therapy of patients with advanced adenocarcinoma of the lung in a phase 2 study.
Methods:
GALAXY-2 is a randomized (1:1), international, open-label study of D with or without G. Patients with advanced (stage IIIB/IV) non-small cell lung cancer (NSCLC) of adenocarcinoma histology, EGFR and ALK wild-type, diagnosed ≥ 6 months prior to study entry, one prior systemic therapy and ECOG PS 0-1 were eligible. D was given at 75 mg/m[2] on day 1 of three-week cycle; D was given on day 1 with G at 150 mg/m[2 ]on Days 1 and 15 of each cycle. Patients were stratified by performance status (PS), LDH, and geographic region. Primary endpoint was overall survival (OS). Secondary endpoints included progression free survival (PFS) and OS in elevated LDH (eLDH) patients. We report the results of a planned interim analysis at 336 events, which occurred on October 5, 2015, with type I error level set at 0.01 (2 sided stratified log-rank test).
Results:
677 patients were randomized with 335 patients in G+D arm and 337 patients in D arm. Baseline characteristics: females 60%, age < 65 68%; never-smoker 18%; PS 0 36%; eLDH 29%; North America/Western Europe 39%. The median number of cycles delivered was 5 in G+D and 4 in D arm. There was no difference in median OS (mOS) for the two arms: 10.9 months with G+D versus 10.5 months with D alone. The hazard ratio for OS was 1.111 (95% CI 0.899-1.372), which met the early stopping criteria for futility. Median PFS was similar in the two arms: 4.2 versus 4.3 months, G+D and D, respectively (HR 1.161, 95% CI 0.961-1.403). There was no improvement with the addition of G for any secondary endpoint, including survival in the eLDH and EGFR and ALK negative populations, response rate, or progression due to new metastatic lesions. The most common grade 3/4 treatment-emergent adverse event in both arms was neutropenia (31.1% versus 24.3%, G+D and D, respectively).
Conclusion:
The addition of ganetespib to docetaxel did not result in improved efficacy for salvage therapy of patients with advanced stage lung adenocarcinoma.
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PL04a - Plenary Session: Immune Checkpoint Inhibitors in Advanced NSCLC (ID 430)
- Event: WCLC 2016
- Type: Plenary
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:J. Soria, C. Zhou
- Coordinates: 12/07/2016, 08:45 - 09:40, Hall D (Plenary Hall)
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PL04a.02 - OAK, a Randomized Ph III Study of Atezolizumab vs Docetaxel in Patients with Advanced NSCLC: Results from Subgroup Analyses (Abstract under Embargo until December 7, 7:00 CET) (ID 5822)
08:55 - 09:05 | Author(s): D. Kowalski
- Abstract
- Presentation
Background:
Atezolizumab inhibits PD-L1 binding to its receptors PD-1 and B7.1, thereby restoring tumor-specific T-cell immunity. Primary analysis of the Phase III OAK study in previously-treated NSCLC revealed superior survival for atezolizumab vs docetaxel in the ITT population (mOS, 13.8 vs 9.6 months; HR, 0.73) and in patients expressing ≥1% PD-L1 on TC or IC (TC1/2/3 or IC1/2/3; mOS, 15.7 vs 10.3; HR, 0.74). Here we present further subgroup analyses.
Methods:
OAK evaluated atezolizumab vs docetaxel in an unselected NSCLC population who had failed prior platinum-containing chemotherapy. Patients were stratified by PD-L1 expression, prior chemotherapy regimens and histology, and randomized 1:1 to atezolizumab (1200 mg) or docetaxel (75 mg/m[2]) IV q3w. PD-L1 expression by IHC and mRNA was centrally evaluated by VENTANA SP142 IHC assay and Fluidigm, respectively. Data cutoff, July 7, 2016.
Results:
For the first 850 of 1225 randomized patients (primary study population), OS was improved with atezolizumab vs docetaxel regardless of histology and this benefit was observed across PD-L1 subgroups within each histology (Table). PD-L1 gene expression showed a similar association with OS as PD-L1 IHC. In nonsquamous patients ORR was 14.4% vs 15.2%; in squamous patients ORR was 11.6% vs 8.2% (atezolizumab vs docetaxel). OS benefit vs docetaxel was seen across subgroups including patients with treated baseline brain metastases (n=85; mOS 20.1 vs 11.9 mo; HR 0.54, 95% CI 0.63-0.89) and never smokers (n=156; mOS 16.3 vs 12.6 mo, HR 0.71, 95% CI 0.47-1.08). Further secondary endpoints and exploratory biomarker analyses for these subgroups and by age and EGFR/KRAS status will be presented.
Conclusion:
OAK demonstrated clinically relevant improvements with atezolizumab in the ITT population, including in both histology subgroups regardless of PD-L1 expression (measured by IHC or tumor gene expression), and among other subgroups including never smokers and in patients with baseline brain metastases.OS Atezolizumab Docetaxel HR[a]95% CI n Median, mo n Median, mo Nonsquamous TC3 or IC3 49 22.5 47 8.7 0.35(0.21-0.61) TC2/3 or IC2/3 89 18.7 99 11.3 0.61(0.42-0.88) TC1/2/3 or IC1/2/3 171 17.6 162 11.3 0.72(0.55-0.95) TC0 and IC0 140 14.0 150 11.2 0.75(0.57-1.00) All 313 15.6 315 11.2 0.73(0.60-0.89) Squamous TC3 or IC3 23 17.5 18 11.6 0.57(0.27-1.20) TC2/3 or IC2/3 40 10.4 37 9.7 0.76(0.45-1.29) TC1/2/3 or IC1/2/3 70 9.9 60 8.7 0.71(0.48-1.06) TC0 and IC0 40 7.6 49 7.1 0.82(0.51-1.32) All 112 8.9 110 7.7 0.73(0.54-0.98) [a]Unstratified HRs. TC=tumor cell, IC=tumor-infiltrating immune cell
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