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L. Seymour
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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 10.01 - Durvalumab ± Tremelimumab with Platinum-Doublets in Non-Small Cell Lung Cancer: Canadian Cancer Trials Group Study IND.226 (ID 8700)
11:00 - 12:30 | Author(s): L. Seymour
- Abstract
- Presentation
Background:
Anti-PD1-monotherapy has activity in NSCLC with improved outcomes compared to chemotherapy. Preclinical, and early clinical data, suggests that combining immune checkpoint inhibitors and platinum-based chemotherapy may be synergistic. We examined the cohort of patients (pts) with metastatic NSCLC, with no prior therapy for advanced disease, from this multicentre phase Ib trial. The primary objective was to establish the recommend phase II doses of durvalumab (Du) ± tremelimumab (Tr) in combination with platinum-doublet chemotherapy. Secondary objectives included assessing safety, tolerability, and antitumour activity of the 4-drug combination.
Method:
Pts were treated with Du±Tr at one of 4 dose levels (DL) concomitantly with either pemetrexed (Pem) +cisplatin/carboplatin followed by maintenance Pem for nonsquamous histology or gemcitabine (Gem) +cisplatin/carboplatin for squamous tumours. At DL0 Du 15 mg/kg IV q3wks was added; DL1 added Du 15mg/kg q3wk + Tr 1mg/kg x1 dose; DL2a added Du 15mg/kg q3wk + Tr 1 mg/kg q6wk x multiple doses; DL2b added Du 15mg/kg q3wk + Tr 3 mg/kg q6wk (1 dose with cycle 1 and 2 doses with maintenance pem), DL3 and DL4 added a fixed doses of Du 1125mg/Tr 56 mg and Du 1500 mg/ Tr 75 mg q3wk respectively. Du could continue until 1 year or unacceptable toxicity.
Result:
To date, 45 pts (median age=62 (range 36-78); 44% male, 100% ECOG PS≤1) have received 346 cycles in the Pem-platinum cohort while 9 pts (median age=64 (range 57-80); 78% male, 100% ECOG PS≤1) have been received 55 cycles in the Gem-platinum group. Most adverse events were ≤grade 2 and attributed to chemotherapy. Immunotherapy-related adverse events (irAEs) ≥ grade 3 were observed in 27% of patients and were more commonly reported with the addition of Tr. In the Pem-platinum cohort, diarrhea (n=5), fatigue (n=4) and elevated lipase (n=4) were the most come irAEs ≥ grade 3, while rash, pneumonitis and hypothyroidism occurred in 1 pt each after the introduction of Tr. In the Gem-platinum cohort, irAEs ≥ grade 3 were fatigue and rash (1 pt each at DL2b) and elevated lipase (1 pt at DL3). The objective response rate in 35 evaluable patients receiving Pem-platinum was 57.1% (95% CI=39.4, 73.7 ) and 37.5% (95% CI=8.5, 75.5) in the 8 evaluable patients receiving Gem-Platinum.
Conclusion:
The combination of Du±Tr can be safely administered with platinum-doublet chemotherapy with encouraging preliminary response data. Adding Tr may increase ≥ grade 3 irAE hence patient selection and early intervention is key to managing irAEs. *contributed equally
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P2.01 - Advanced NSCLC (ID 618)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 10/17/2017, 09:00 - 16:00, Exhibit Hall (Hall B + C)
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P2.01-032 - A Randomized Phase Ii Trial of Selumetinib + Platinum-pemetrexed (Pem-c) in Kras Wildtype (Wt)/Unknown NSCLC: CCTG Ind219 (ID 9083)
09:00 - 16:00 | Author(s): L. Seymour
- Abstract
Background:
Selumetinib (SEL), an oral inhibitor of MEK 1 and 2, could be particularly effective in tumours with an activated Ras/Raf/MEK/ERK pathway, but has not been fully studied in KRAS WT nor in the first-line setting. The scheduling of SEL with chemotherapy might impact efficacy and/or toxicity.
Method:
IND219 is an open-label three-arm study of PEM-C±SEL. Arm A: PEM-C+SEL days 2-19; Arm B: PEM-C+SEL days 1-21; Arm C: PEM-C alone. Primary objective was response rate (ORR); secondary objectives were tolerability and progression-free survival (PFS). Pts were stratified by KRAS WT versus unknown and cisplatin versus carboplatin. Before the planned interim analysis (60 pts), pts were allocated 1:1:1 to arm A, B or C, with a plan to continue either Arm A or B plus Arm C a 3:1 ratio to ensure that the final analysis includes Arm A or B and Arm C in a 2:1 ratio. The trial would stop if neither Arm A or B had > 4 responses; if both did, the arm would be selected based on response and toxicity data. Correlative studies included genomic testing.
Result:
Arm A/B/C enrolled 20/21/21 pts. PEM-C exposure was lower with SEL (median cycles 5 versus 6 for Arm C). Seven pts on Arm A (35%; 95% CI 15-59% median duration 3.8m), 13 on Arm B (62%; 95% CI 38-82%; median duration 6.3m), and 5 on Arm C (24%; 95% CI 8-47%; median duration 11.6m) had PR, meeting the criteria to continue. PFS was 7.5m (95% CI 4.0 to 9.0 m) for Arm A, 6.7m (95% CI 4.1 to 8.2 m) on Arm B, and 4.0m on Arm C (95% CI 1.4 to 6.8 m). HR for PFS of Arm A over Arm C was 0.76 (95% CI 0.38 to 1.51, 2-sided p=0.42); HR for PFS of Arm B over Arm C was 0.75 (95% CI 0.37 to 1.54, p=0.43). After adjusting for age, performance status, gender and KRAS, PFS comparisons remained NS. Toxicity was most commonly grade 1-2, but more frequent with SEL especially mucositis, diarrhea, anorexia, dehydration, edema and rash. A high rate of venous thromboembolism (VTE) was seen in all arms, highest in Arm A (Arm A 45 % versus 14 % [p=0.11])
Conclusion:
SEL+PEM-C is associated with higher, but less durable ORR. In this small study, PFS is numerically prolonged adding SEL to PEM-C with expected additive toxicity. Further exploration of these intriguing results is ongoing.
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P2.01-055 - Examining Metabolomics as a Prognostic Marker in Metastatic Non–Small Cell Lung Cancer Patients Undergoing First-Line Chemotherapy (ID 8685)
09:00 - 16:00 | Author(s): L. Seymour
- Abstract
Background:
The metabolome represents the endpoint of many cellular events; hence patients' baseline metabolomic profile may reveal specific prognostic markers of overall survival. In this study, we sought to characterize the serum metabolite signatures in patients with metastatic non-small cell lung cancer (mNSCLC) who underwent first-line therapy, using nuclear magnetic resonance (1H-NMR) spectroscopy and liquid chromatography mass spectrometry (LC-MS), and to explore their potential prognostic impact.
Method:
Serum samples were collected prospectively as part of a clinical trial in which patients were treated with systemic therapy including platinum-doublet chemotherapy. For each method of analysis, samples were divided into training (3/5) and validation (2/5) sets stratified by treatment received, stage (III vs. IV), and ECOG PS (0, 1, vs. ≥ 2). Exploratory analyses were performed to characterize the relationships between baseline lipid and polar levels and overall survival. Kaplan-Meier curves were used to estimate the distributions of time to event outcomes, and a Cox regression model was used to correlate marker levels while adjusting for baseline characteristics.
Result:
Using 1H-NMR, 16 out of 43 metabolites were significantly correlated with overall survival (OS) by univariate analysis (p < 0.025) and 4 metabolites were included in the final multivariate model. The median OS was 11.4 months in the low risk group vs. 6.6 months in the high risk group (HR=1.99, 95% C.I. 1.45 – 2.68; p<0.0001). Using LC-MS, 53 lipid species were correlated with OS by univariate analysis. Variables were then subjected to hierarchical cluster analysis resulting in 12 branches which were moderately to significantly correlated with lipid features. Principle component analysis (PCA) was performed and the first PC from each such branch was used (n=9). Using Cox regression modeling, median OS was 5.7 months vs. 11. 9 months for the low and high risk groups respectively, even after adjusting for baseline characteristics (HR: 2.23, 95% C.I. 1.55 – 3.20; p< 0.0001).
Conclusion:
Metabolite profiles from baseline pre-treatment serum samples have the potential to act as prognostic markers in patients with mNSCLC undergoing first-line chemotherapy. Serial metabolite measurements pre- and post-treatment may yield additional information and provide enhanced data for predicting clinical outcomes.
