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W.E.E. Eberhardt
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ED 10 - Controversies in Stage IIIA Disease (ID 10)
- Event: WCLC 2015
- Type: Education Session
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:C.P. Belani, E. Vokes
- Coordinates: 9/09/2015, 14:15 - 15:45, 201+203
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ED10.03 - Induction Chemotherapy as an Investigational Strategy (ID 1812)
14:15 - 15:45 | Author(s): W.E.E. Eberhardt
- Abstract
- Presentation
Abstract:
Introduction: Standard treatment of stage IIIA non-small-cell lung cancer consists of definitive concurrent chemoradiotherapy (CTx/RTx) protocols. Based on the broad heterogeneity of stage IIIA alone, there are selected patients (single mediastinal lymph node involvement, IIIA3 Robinson) where induction chemotherapy (CTx) followed by definitive surgery may be an alternative and valid approach preferably to test within prospective clinical trials with a close documentation of the toxicity/efficacy ratio. Patients and Methods: The medical literature (PUBMED) was reviewed looking for the search terms “induction chemotherapy“ and “stage III“ and “non-small cell lung cancer“. Furthermore large clincal trials were added that had been presented at important clinical conferences such as ASCO, WCLC and ESMO. Prospective phase-III clinical trials and prospective phase-II clinical trials were examined and cathegorized for efficacy and outcome parameters. We looked specifically for general patterns in the reporting of clinical trials results. Results: General outcome parameters for efficacy that have been reported were: 1) objective response rates 2) overall survival (median) 3) progression-free survival rates 4) complete resection rates (R0-resection) 5) pathological complete response rates (pCR) in the primary tumor and 6) pathological complete response rates (pCR) in the mediastinum. On the other hand important benchmarks for toxicity were 1) grade 3 and grade 4 maximum toxicity rates during induction 2) perioperative toxicity rates grade 3 and 4 3) treatment related death rates. Very few investigations have looked at patient reported outcome parameters such as symptom improvement or quality of life evaluation during the complete treatment protocol. Several groups have tried to improve outcome data by the use of 1) three-drug regimen as induction treatment 2) second- and third-generation platinum-based combinations 3) introduction of new molecular targeted agents (VEGF, EGF-R etc) especially looking closely at the pathological complete response rates induced by induction therapy 4) inclusion of different radiation schemas within a concurrent or sequential preoperative application protocols. Several reported trials have also tried to alternatively give a definitive CTx/RTx protocol with increased radiation doses and have not included a definitive surgical approach. These studies could not report data on pathological responses and some have alternatively looked at FDG-PET response to induction therapy as a surrogate marker for pathological response. Currently the treatment protocols with the highest reported pathological response (pCR) rates were based on cisplatinum and taxane (paclitaxel and docetaxel) combinations and induction protocols including concurrent cCTx/RTx regimen were those with the highest pathological efficacy in the mediatinum as well as in the primary tumor. Conclusions and Outlook: With the existing broad heterogeneity in patient selection within the different clinical studies performed it is currently difficult to give an overall recommendation about the most optimal treatment approach in this setting of stage IIIA NSCLC. Induction CTx could potentially serve as a backbone for including new treatment principles (eg. molecular targeted agents, immunotherapy, CTx/RTx protocols) into these multimodality treatment protocols and closely monitoring outcome by translational investigations and pathological response evaluations.
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MINI 18 - Radiation Topics in Localized NSCLC (ID 139)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 1
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MINI18.15 - Discussant for MINI18.11, MINI18.12, MINI18.13, MINI18.14 (ID 3474)
16:45 - 18:15 | Author(s): W.E.E. Eberhardt
- Abstract
- Presentation
Abstract not provided
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ORAL 02 - PD1 Axis Immunotherapy 2 (ID 87)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:E.B. Garon, H.J. Ross
- Coordinates: 9/07/2015, 10:45 - 12:15, Four Seasons Ballroom F1+F2
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ORAL02.01 - Phase 3, Randomized Trial (CheckMate 017) of Nivolumab (NIVO) vs Docetaxel in Advanced Squamous (SQ) Cell Non-Small Cell Lung Cancer (NSCLC) (ID 736)
10:45 - 12:15 | Author(s): W.E.E. Eberhardt
- Abstract
- Presentation
Background:
Treatment options for patients with advanced SQ NSCLC who fail platinum-based doublet chemotherapy (PT-DC) are limited. NIVO, a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor, demonstrates activity across NSCLC histologies and is approved in the US for treatment of metastatic SQ NSCLC with progression on or after platinum-based chemotherapy. We report results from a randomized, open-label, global phase 3 study (CheckMate 017; NCT01642004) comparing NIVO vs docetaxel in patients with previously treated SQ NSCLC and disease progression during/after one prior PT-DC regimen.
Methods:
Patients (N=272) were randomized 1:1 to receive either NIVO 3 mg/kg every 2 weeks (Q2W; n=135) or docetaxel 75 mg/m[2] Q3W (n=137) until disease progression or discontinuation due to toxicity or other reasons. For NIVO patients, treatment after initial progression was permitted at the investigator’s discretion, per protocol criteria. The primary objective was overall survival (OS). Secondary objectives included investigator-assessed objective response rate (ORR; per RECIST v1.1), progression-free survival (PFS), efficacy by PD-L1 expression (PD-L1 testing not required for enrollment), patient-reported outcomes (PRO), and safety. PRO analyses are presented in a separate abstract.
Results:
Treatment with NIVO led to 41% reduction in risk of death (hazard ratio [HR]=0.59; 95% CI: 0.44, 0.79; P=0.00025) and improved ORR (20% vs 9%; P=0.0083) and PFS (HR=0.62; 95% CI: 0.47, 0.81; P=0.0004) vs docetaxel (Table). Twenty-eight patients were treated with NIVO beyond initial progression, nine of whom demonstrated a non-conventional pattern of benefit (ie, reduction in target lesions with simultaneous appearance of new lesions, initial progression followed by tumor reduction, or no further progression for ≥2 tumor assessments). Across pre-specified cut-points (1%, 5%, and 10%), PD-L1 expression was neither prognostic nor predictive of benefit. OS HRs favored NIVO across most predefined patient subgroups. Grade 3–4 drug-related adverse events (AEs) were reported in 7% (9/131) of NIVO and 55% (71/129) of docetaxel patients. Grade 3–4 drug-related select AEs are shown below (Table). No deaths were related to NIVO vs 3 docetaxel-related deaths. Figure 1
Conclusion:
CheckMate 017 achieved its primary objective, demonstrating clinically superior and statistically significant OS with NIVO vs docetaxel in patients with advanced, previously treated SQ NSCLC. Benefit was seen regardless of PD-L1 status. The safety profile of NIVO 3 mg/kg Q2W is favorable vs docetaxel and consistent with prior studies. AEs were manageable with established guidelines. NIVO represents a new standard of care in this patient population. Updated OS and safety data will be presented.
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P1.12 - Poster Session/ Community Practice (ID 232)
- Event: WCLC 2015
- Type: Poster
- Track: Community Practice
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.12-002 - International Online Tool for Therapeutic Decision Making in NSCLC (V2.0) (ID 2160)
09:30 - 17:00 | Author(s): W.E.E. Eberhardt
- Abstract
Background:
Practice guidelines in non-small-cell lung cancer (NSCLC) list multiple therapy choices based on levels of evidence but cannot account for variability in patient (pt)-tumor characteristics between individual patient cases. To provide oncologists with expert guidance and feedback on choice of treatment (Tx) for specific pt scenarios, we previously implemented an interactive Web-based decision support tool in 2012, in which oncologist users input specific pt characteristics and selected among treatment options, then compared their selection with that of an NSCLC expert panel for that scenario. (Chow JTO 2015). Here we report data from version 2.0 of this tool, capturing current Tx trends for advanced NSCLC and investigating the impact of this online tool on oncology practitioners.
Methods:
V2.0 was developed based on input from 6 international NSCLC experts who provided Tx recommendations for 1st-line treatment in 96 pt case variations based on histology (nonsquamous vs squamous), EGFR mutational status (positive [+] vs negative [-]), ALK rearrangement (+ vs -), age (< 70 vs ≥ 70 years), performance status (0, 1 vs 2), smoking history (never/former light vs former heavy/current), and pt primary Tx goal (response and survival vs quality of life and low adverse events). As in V1.0, oncologist users input specific pt scenarios, then were prompted for their treatment choice. Once completed, recommendations for that scenario from each of the experts were displayed, and users were prompted to indicate whether the expert recommendations changed their treatment choice. Statistical methods: as previously described (Chow JTO 2015).
Results:
V2.0 oncologist users (N = 218 unique users) contributing 314 unique cases were 87% non-USA, 13% USA. As in V1.0, experts agreed on selection of targeted therapies (TKIs) for cases with actionable EGFR mutations and ALK translocations. Choice of a specific EGFR inhibitor by experts varied depending on region and clinical factors. By comparison, among online users of V2.0, an EGFR inhibitor was selected for 67% of EGFR-mutated cases (n = 78), while an ALK inhibitor was selected for 61% of ALK cases (n = 31). For nonsquamous histology cases without actionable mutations, use of pemetrexed was more common among experts compared with oncologist users (91% vs 48% of case scenarios). In 182 cases entered by users who reported on the impact of expert recommendations, treatment choice was affected in 86% of cases (confirmed in 71%); 5.5% disagreed with expert recommendations and 8% indicated barriers to implementing the recommendations. In comparing overall results from V1.0 (2012) to V2.0 (2014), more oncologist users were likely to select TKIs in both EGFR mutation (49% vs 67%) and ALK translocation (35% vs 61%), with a corresponding decrease in use of chemotherapy. A detailed analysis of expert vs user data will be presented, comparing V1.0 (2012) and V2.0 (2014).
Conclusion:
Expert opinions were largely unchanged between V1.0 and V2.0, while oncologist users increased use of TKIs. Most oncologist users of V2.0 either confirmed or changed treatment choices based on expert recommendations. This online tool can aid decision making, serve an educational purpose, and capture practice trends.
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P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-089 - Nab-Paclitaxel with or without CC-486 as Second-Line Therapy for NSCLC (ABOUND.2L) (ID 719)
09:30 - 17:00 | Author(s): W.E.E. Eberhardt
- Abstract
Background:
Many patients with advanced non-small cell lung cancer (NSCLC) will experience disease progression during first-line chemotherapy. Effective and well-tolerated second-line treatment options for this patient population are limited. In a multicenter phase III trial, first-line treatment with nab-paclitaxel plus carboplatin (nab-P/C) significantly improved the primary endpoint of overall response rate (ORR) compared with solvent-based paclitaxel plus C in patients with advanced NSCLC (33% vs 25%; P = 0.005; Socinski et al. J Clin Oncol. 2012;30:2055-2062). nab-P combined with CC-486, an oral formulation of azacitidine, resulted in promising outcomes in a phase I trial of patients with relapsed/refractory solid tumors (LoRusso et al. Mol Cancer Ther. 2013;12(11 Suppl):Abstract A120). In the open-label, multicenter phase II ABOUND.2L trial, the safety and efficacy of nab-P with or without CC-486 will be evaluated in the second-line treatment of patients with advanced nonsquamous NSCLC.
Methods:
Approximately 160 patients who have received 1 platinum-containing chemotherapy regimen for treatment of advanced disease will be randomized 1:1 to CC-486 200 mg/day on days 1 to 14 every 21 days plus nab-P 100 mg/m[2] intravenously (IV; 30-minute infusion) on days 8 and 15 every 21 days or nab-P 100 mg/m[2] IV (30-minute infusion) on days 1 and 8 every 21 days. Key eligibility criteria include histologically or cytologically confirmed advanced nonsquamous NSCLC, ECOG performance status ≤ 1, adequate organ function, no active brain metastases, no prior taxane therapy, no known EGFR mutation or EML4-ALK translocation, and peripheral neuropathy grade < 2. Randomization will be stratified by ECOG performance status (0 vs 1), sex, and smoking status (yes vs no). ClinicalTrials.gov identifier NCT02250326.Key Endpoints
Primary -Progression-free Survival Secondary -Disease control rate -Overall Survival -ORR -Safety Exploratory -Changes in quality of life -Healthcare resource utilization throughout the study -Correlation between pretreatment tumor characteristics and response to treatment
Results:
Not applicable
Conclusion:
Not applicable
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P3.03 - Poster Session/ Treatment of Locoregional Disease – NSCLC (ID 214)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.03-018 - Intercalated TKI and Chemotherapy Induction in EGFR mt+ NSCLC Stage IIIA and IIIB: 3 Cases with Complete Remission in Mediastinal Lymph Nodes (ID 3223)
09:30 - 17:00 | Author(s): W.E.E. Eberhardt
- Abstract
Background:
EGFR TKI treatment is standard of care in patients with metastasized NSCLC carrying an activating EGFR mutation. However, induction concepts in locally advanced NSCLC with EGFR mutation including TKI have not been studied extensively. Recently new focus has been shed on intercalated regimens of chemotherapy and TKI, showing improved PFS as well as OS. This concept was used as induction regimen in 3 patients with activating EGFR mutation in stages IIIA and IIIB.
Methods:
Patients were diagnosed and worked up according to standard imaging, histology and immunohistology methods. EGFR, KRAS, BRAF, ALK and P53 mutation analysis were performed with standard procedures as described by Halbfass et al. 2013. Remission induction was measured by RECIST 1.1, regression grading by Junker criteria.
Results:
2 female never smokers (pt #1 and 3), 62 and 59 y.o. and 1 male light smoker (pt#2) (5 packyear), 58 y.o . were diagnosed with with TTF1+ adenocarcinoma of the lung, 2 with exon 21 L858R (#2,3) and 1 with Exon 19 deletion (#1). All patients carried a p53 mutation, exon 6 (#2,3), exon 8 (#1). Tumor stage was T (extension to mediastinal pleura) N2 (2R, 4R) M0, IIIA4 (#1), T2aN3(4L,7,2R)M0 IIIB (#2) and T2N3M0. Induction therapy was started with erlotinib 150 mg/die p.o. days -12 to -1 (#1,2) and gefitinib (#3) in order to prove responsiveness of the tumor to EGFR-TKI. On day 0 partial response or no progression was achieved in all 3 patients. Therapy was continued with 3 cycles of docetaxel 75 mg/m2 d1 and cisplatin 50 mg/m2 d1 and 2 qd22 in combination with erlotinib d4-19 (#1), 1 cycle of docetaxel and cisplatin followed by 2 cycles of paclitaxel and carboplatin (#2) and switch from erlotinib to gefitinib with cycle 2 (#2) because of diarrhea) and 3 cycles of docetaxel and cisplatin with gefinitib 250 mg d4-19 (#3). PR was was achieved after 2 cycles in all patients. All three patients were resected and regression grade IIB was remarked in mediastinal lymph nodes (#1-3), regression IIA was remarked in the primary tumor in 2 patients (#2,3), regression grade III in 1 patient (#1). All three patients received adjuvant radiotherapy. Patients #1 and 3 are in CR, patient 2 developed one isolated CNS metastasis which has been stereotactically irradiated. No additional therapy, including TKI was administered postoperatively.
Conclusion:
Intercalated TKI treatment is a promising treatment choice in patients with EGFR mt+ locally advanced NSCLC. A phase II trial (NeoIntercal) trial is currently under way in 9 German centers in stages II and III using gefitinib in combination with induction taxane based chemotherapy, supported by ASTRA Zeneca.
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-005 - Discrepancies between ALK FISH and Capture Based NGS Test NEOplus and Clinical Outcome with ALK TKI Therapy (ID 2748)
09:30 - 17:00 | Author(s): W.E.E. Eberhardt
- Abstract
Background:
Research in recent years has unraveled several gene fusions driving tumor development in lung cancer. Especially adenocarcinomas of the lung harboring ALK and ROS1 gene fusions exhibit striking sensitivity to ALK and ROS1 kinase inhibitors respectively, translating to dramatic responses in the clinic. Several different technologies are available to detect aberrant genomic structures. The most frequently used technologies include fluorescent in situ hybridization (FISH), currently considered as the “gold standard”, immunohistochemistry (IHC), RT-PCR based approaches and hybrid capture based NGS sequencing.
Methods:
Here, we describe a selection of tumor samples showing discrepant results between fluorescent in situ hybridization and hybrid capture based NGS sequencing. These included samples with positive FISH but negative NEOplus as well as negative FISH and positive NEOplus results. In addition, we used response data of targeted therapies to evaluate the true genetic phenotype of the tumor.
Results:
Overall, several lung adenocarcinomas showed discrepant results when FISH and NEOplus data were compared. First, one sample was tested positive for ALK rearrangement using FISH which was not confirmed using NEOplus. In line with this finding, the tumor did not respond to ALK TKI treatment. Second, a total of 4 cases were fusion negative by FISH but positive by NEOplus. Three out of 4 ALK positive cases showed clinical response to ALK kinase inhibition, the clinical results for case number 4 are pending. Interestingly, one of these responding tumors was also negative for ALK expression using IHC.
Conclusion:
In summary, we describe a selection of tumor samples with discrepant results for fusion detecting using FISH and NEOplus. Overall, in all of the cases for which clinical response data was available, tumor sensitivity was in line with the initial diagnosis generated by the NEOplus assay.
