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Pieter E. Postmus
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MA 03 - Chemotherapy (ID 651)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Jin-Hyoung Kang, W. Su
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 502
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MA 03.01 - Nab-Paclitaxel ± CC-486 as Second-Line Treatment of Advanced NSCLC: Results from the ABOUND.2L+ Study (ID 8676)
11:00 - 11:05 | Author(s): Pieter E. Postmus
- Abstract
- Presentation
Background:
CC-486 (oral azacitidine) is an epigenetic modifier with potential effect as a priming agent for chemotherapy in patients with NSCLC. Outcomes of nab-paclitaxel+CC-486 vs nab-paclitaxel as second-line treatment of advanced NSCLC are reported.
Method:
Patients with advanced nonsquamous NSCLC and no more than 1 prior chemotherapy line (including platinum doublet combination) were randomized (1:1) to nab-paclitaxel 100 mg/m[2] d8, 15 + CC-486 200 mg qd d1-14 or nab-paclitaxel 100 mg/m[2] d1, 8, both administered q3w until progressive disease/unacceptable toxicity. Primary endpoint was PFS. Secondary endpoints: DCR, ORR, OS, and safety. QoL, an exploratory endpoint, was assessed on d1 of each cycle.
Result:
The nab-paclitaxel+CC-486 arm was discontinued in October 2016 due to demonstrated futility vs nab-paclitaxel monotherapy upon completion of a protocol-specified interim analysis. Overall, 161 patients were randomized (nab-paclitaxel+CC-486, 81; nab-paclitaxel, 80). Baseline characteristics were balanced between arms. The median number of cycles was 4 for each arm, and the median nab-paclitaxel cumulative dose was 600 mg/m[2] and 800 mg/m[2] in the nab-paclitaxel+CC-486 and nab-paclitaxel arms, respectively. Rates of grade 3/4 (G3/4) treatment-emergent AEs were 59.5% and 54.4% for the combination and monotherapy arms, respectively. The most frequent hematologic G3/4 AEs were neutropenia (16.5% vs 10.1%) and anemia (1.3% vs 7.6%). G3/4 peripheral neuropathy was reported in 2.5% and 7.6% of patients, respectively. The addition of CC-486 to nab-paclitaxel did not improve ORR, DCR, PFS, or OS (Table). When assessed by Lung Cancer Symptom Scale, nab-paclitaxel monotherapy was associated with improvement in the global QoL, average symptom burden index, and lung cancer symptoms except for hemoptysis.
Conclusion:
The addition of CC-486 to nab-paclitaxel did not clinically benefit patients with previously treated NSCLC. However, single-agent nab-paclitaxel appears to be a promising therapy based on safety, efficacy, and QoL data. Updated efficacy and safety data will be presented. NCT02250326nab-Paclitaxel + CC-486 n = 81 nab-Paclitaxel n = 80 Median PFS, months 3.2 4.2 HR (95% CI) 1.3 (0.9 - 2.0) 1-year PFS, % 4.1 18.3 Median OS, months 8.4 12.7 HR (95% CI) 1.4 (0.88 - 2.31) 1-year OS, % 39.2 54.3 ORR, n (%)[a] 11 (13.6) 11 (13.8) Response rate ratio (95% CI) 0.99 (0.45 - 2.15) CR PR SD PD DCR (≥ SD) 0 11 (13.6) 41 (50.6) 22 (27.2) 52 (64.2) 0 11 (13.8) 43 (53.8) 19 (23.8) 54 (67.5) CR, complete response; DCR, disease control rate; HR, hazard ratio; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease. [a] Response rate was based on the intent-to-treat population; however, 14 patients did not have a response assessment.
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MA 10 - Immunotherapy I (ID 664)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:S. Wang, Robert Pirker
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 303 + 304
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MA 10.02 - Nab-Paclitaxel + Durvalumab as Second- or Third-Line Treatment of Advanced NSCLC: Results from ABOUND.2L+ (ID 8682)
11:05 - 11:10 | Author(s): Pieter E. Postmus
- Abstract
- Presentation
Background:
Chemotherapy may enhance immunotherapeutic effects by causing tumor antigen release, which primes the immune system to kill tumor cells. Early clinical data on nab-paclitaxel + carboplatin in combination with immune checkpoint inhibitors (ICI) demonstrated promising activity without compounding toxicities in patients with non-small cell lung cancer (NSCLC). ABOUND.2L+ evaluated nab-paclitaxel–based regimens in previously treated patients with advanced NSCLC. Here we report the efficacy and safety of nab-paclitaxel + durvalumab as second/third-line treatment.
Method:
Patients with advanced NSCLC were assigned to receive second/third-line (immunotherapy allowed in prior line, including platinum doublet combination) nab-paclitaxel 100 mg/m[2] on days 1 and 8 + durvalumab 1125 mg on day 15, in 21-day cycles, administered until unacceptable toxicity/progression per immune-related RECIST v1.1. Primary endpoint is progression-free survival (PFS). Secondary endpoints are overall survival (OS), overall response rate (ORR), disease control rate (DCR), and safety.
Result:
Seventy-nine patients were enrolled. Median age was 63 years, 68% of patients were male, 23% had Eastern Cooperative Oncology Group performance status of 0, and 70% had nonsquamous NSCLC; 11% of patients received prior ICIs. Median PFS (Table) and OS were 4.5 (3.4-5.8) months and NE (7.3-NE). ORR was 27% (1 complete response) and DCR was 71%. Grade 3/4 treatment-emergent adverse events of special interest occurring in ≥ 5% of patients included neutropenia (6%) and dyspnea (5%); grade 3/4 peripheral neuropathy and anemia each occurred in 4% of patients. Median treatment duration was 24 weeks; median number of treatment cycles was 7. For nab-paclitaxel and durvalumab, median dose intensities were 59.05 mg/m[2]/week and 326.61 mg/week, respectively; median percentages of per-protocol dose were 88.58% and 87.10%.
Conclusion:
The combination of durvalumab with nab-paclitaxel demonstrated antitumor activity with manageable toxicity in the second/third-line setting. Further details will be presented. NCT02250326Nab-P Durva Median PFS (range), months Overall (n = 79) 4.5 (3.4-5.8) ICI pretreated (n = 9)[a] ICI naive (n = 69)[a] 6.9 (1.4-NE) 4.4 (3.0-5.7) Squamous (n = 23)[a] Nonsquamous (n = 55)[a] 5.9 (3.0-7.8) 4.2 (2.9-5.7) ICI, immune checkpoint inhibitor; NE, not estimable; PFS, progression-free survival. [a] Data pending for 1 patient.
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MS 24 - Management of GGO-Containing Nodule (ID 546)
- Event: WCLC 2017
- Type: Mini Symposium
- Track: Radiology/Staging/Screening
- Presentations: 1
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MS 24.05 - Possibility of Chemotherapy for GGO-Containing Tumors (ID 7758)
14:50 - 15:10 | Author(s): Pieter E. Postmus
- Abstract
- Presentation
Abstract:
The radiological term GGO or ground-glass opacity was established when high-resolution CT (HRCT) became part of standard practice, and describes “a hazy attenuation of lung, with preservation of bronchial and vascular margins: caused by partial filling of air spaces, interstitial thickening, partial collapse of alveoli, normal expiration, or increased capillary blood volume…” (1). As such GGO is a nonspecific finding but depending on the clinical circumstances it may suggest a specific diagnosis and have consequences for the diagnostic and therapeutic approach. Most primary lung tumours present with masslike areas of consolidation, however there are other patterns. A specific subtype of adenocarcinoma may present as GGO, and this was described as bronchioloalveolar carcinoma (BAC) (2). It reflects the unique lepidic growth pattern along the alveolar septa with a relative lack of acinar filling. The classification BAC was used for a broad spectrum of tumours including small non-invasive peripheral lung tumours, invasive adenocarcinoma with minimal invasion, mixed subtype invasive adenocarcinoma, mucinous and nonmucinous subtypes, and widespread disease. As in this larger group GGO is present in only a minority, it is difficult to conclude from the chemotherapy trials done specifically in BAC (3) what the efficacy of chemotherapy in tumours with as feature GGO is, nor has the pathological feature of lepidic growth been reported in these studies. Overall the response rate in BAC of single agents seems not to be different from other types of NSCLC. At a later stage, it seemed that gefitinib was especially effective in the non-mucinous subtype (4), in retrospect this might be explained by the molecular characteristics of both. EGFR mutation was more related to lepidic growth, whereas KRAS was especially found in mucinous types (5). It became clear that the term BAC leads to confusion and is representing a very heterogeneous group of tumours. It was therefore recommended to discontinue the use of the term BAC (6), and use a more descriptive classification based on histological findings. Within this new grouping the radiological description of ground-glass opacity was related to the pathological pattern of adenocarcinoma: pure GGO would favour adenocarcinoma in situ (AIS) or possibly minimally invasive adenocarcinoma (MIA), and GGO with a solid component > 5 mm in diameter would favour lepidic adenocarcinoma (7). The natural course of pure GGO or GGO with a small solid component is rather benign. In a large Japanese cohort followed for 4.3 + 2.5 years (mean) the frequency of change from pure GGO towards a - still small - solid component was found in 6.6% (69 out of 1046), of the cases initially diagnosed with a very small solid component change into part-solid nodules was seen in almost 20% (16 of 81) (8). All these observations come from resected tumours and cannot be diagnosed in small biopsies, this makes it difficult to characterize more advanced adenocarcinoma in the same way. The likely most GGO containing advanced tumours will be those diagnosed with (dominant) lepidic growth (9). Reports of chemotherapy efficacy are infrequent but do not show a real difference in sensitivity if treated with one of the commonly used regimens carboplatin – paclitaxel (10). Although the LACE-Bio study contains only small numbers of cases with lepidic growth, combining these patients with the ones with the prognostically less unfavourable histology (papillary, acinar) failed to demonstrate benefit of adjuvant chemotherapy (11). The frequency of finding more than one GGO (with or without a solid component) is rather high and reported as almost 30% (12). If this is in a patient with stage IV NSCLC it is questionable whether these are separate primaries or metastases. The behaviour of these lesions has not been systematically reported, personal observations confirm the rather indolent role of these lesions, usually without any pathological proof of malignancy, and no change during systemic therapy for an other stage IV tumour. The question whether the presence of GGO as such, either as part of the stage IV tumour or as a different lesion, should affect the choice of systemic therapy can not be answered. References: 1. Austin JHM, Müller NL, Friedman PJ et al. Glossary of terms for CT of the lungs: recommendations of the Nomenclature Committee of the Fleischner Society. Radiology 1996; 200: 327-331. 2. Jang HJ, Lee KS, Kwon OJ et al. Bronchioloalveolar carcinoma: focal area of ground-glass attenuationat thin-section CT as an early sign. Radiology 1996; 199: 485-488. 3. Miller VA, Hirsch FR, Johnson DH. Systemic Therapy of Advanced Bronchioloalveolar Cell Carcinoma: Challenges and Opportunities. J Clin Oncol 2005; 23:3288-3293 4. Cadranel J, Quoix E, Baudrin L et al. IFCT-0401 Trial. A Phase II Study of Gefitinib Administered as First-Line Treatment in Advanced Adenocarcinoma with Bronchioloalveolar Carcinoma Subtype. J Thorac Oncol. 2009;4: 1126–1135. 5. Yoshizawa A, Sumiyoshi S, Sonobe M et al. Validation of the IASLC/ATS/ERS lung adenocarcinoma classification for prognosis and association with EGFR and KRAS gene mutations: analysis of 440 Japanese patients. J Thorac Oncol. 2013; 8: 52-61 6. Travis WD, Brambilla E, Noguchi M et al. International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 2011; 6: 244-85 7. Travis WD, Brambilla E, Nicholson AG, et al. The 2015 World Health Organization Classification of Lung Tumours: impact of genetic, clinical and radiologic advances since the 2004 classification. J Thor Oncol 2015; 10: 1243-1260. 8. Kakinuma R, Noguchi M, Ashizawa K et al. Natural History of Pulmonary Subsolid Nodules: A Prospective Multicenter Study. J Thorac Oncol 2016; 11: 1012-1028. 9. Travis WD, Asamura H, Bankier AA et al. The IASLC lung cancer staging project: proposals for coding T categories for subsolid nodules and assessment of tumor size in part-solid tumors in the forthcoming eighth edition of the TNM classification of lung cancer. J Thor Oncol 2016; 11: 1204-1223. 10.Cadranel J, Gervais R, Merle P et al. Erlotinib versus carboplatin and paclitaxel in advanced lepidic adenocarcinoma: IFCT-0504. Eur Respir J 2015; 46: 1259–1261. 11. Tsao MS, Marguet S, Le Teuff G et al. Subtype classification of lung adenocarcinoma predicts benefit from adjuvant chemotherapy in patients undergoing complete resection. J Clin Oncol 2015; 33: 3439-3446. 12. Kim HK, Choi YS, Kim J et al. Management of Multiple Pure Ground-Glass Opacity Lesions in Patients with Bronchioloalveolar Carcinoma. J Thorac Oncol. 2010;5: 206–210.
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OA 05 - Next Generation TKI (ID 657)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:James Chih-Hsin Yang, Fiona Blackhall
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 301 + 302
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OA 05.07 - Efficacy and Updated Safety of Ceritinib (450 Mg or 600 Mg) with Low-Fat Meal vs 750 Mg Fasted in ALK+ Metastatic NSCLC (ID 9366)
16:50 - 17:00 | Author(s): Pieter E. Postmus
- Abstract
- Presentation
Background:
Ceritinib is a next-generation anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of patients with ALK+ non-small cell lung cancer (NSCLC) who are treatment-naive or have progressed on crizotinib at the recommended dose of 750 mg/day under fasted state. Gastrointestinal (GI) adverse events (AEs), eg, diarrhea, nausea, vomiting, are common with ceritinib 750 mg/day under fasting conditions. ASCEND‑8 study, (NCT02299505) evaluated alternative methods of ceritinib administration, utilizing potential benefit of dosing ceritinib with food to reduce GI toxicity, while maintaining the pharmacokinetic exposure at lower doses. Based on the primary pharmacokinetics analysis previously presented (n=137; WCLC 2016), ceritinib 450 mg with food had similar exposure and a more favorable GI safety profile vs ceritinib 750 mg fasted in patients with ALK+ NSCLC.
Method:
This is a multicenter, randomized, 3-arm (450 mg or 600 mg ceritinib taken with low-fat meal vs 750 mg ceritinib taken in fasted state), open-label, phase 1 study (ASCEND-8). Patients were eligible if they had stage IIIB or IV ALK+ advanced NSCLC, were aged 18 years or older, who were either previously treated with chemotherapy and/or crizotinib or treatment naive. We plan to report the updated safety (n=228) and preliminary efficacy for treatment-naïve patients (ALK+ by immunohistochemistry [IHC]) who were randomized at least 18 weeks before the cutoff date (March 28, 2017; n=79). Updated analysis is planned to be made available by August 2017 and the following data will be included at the time of final abstract submission: patient disposition; patient demographics; disease characteristics and prior therapies; overall response rate and duration of response by blinded independent review committee (BIRC; key secondary endpoints) in treatment-naïve patients (ALK+ by IHC) randomized at least 18 weeks prior to the cut-off date; progression-free survival per BIRC in treatment-naïve patients (ALK+ by IHC) randomized at least 18 weeks prior to the cut-off date; updated safety results with detailed information on GI (diarrhea, nausea, vomiting) and liver (alanine transaminase/aspartate transaminase) toxicities.
Result:
LBA shell - not applicable
Conclusion:
LBA shell - not applicable
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