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D. Rodríguez-Abreu
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OA 17 - Immunotherapy II (ID 683)
- Event: WCLC 2017
- Type: Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Yuichiro Ohe, Anne Tsao
- Coordinates: 10/18/2017, 14:30 - 16:15, Room 301 + 302
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OA 17.06 - Updated Analysis of KEYNOTE-024: Pembrolizumab vs Platinum-Based Chemotherapy for Advanced NSCLC With PD-L1 TPS ≥50% (ID 9582)
15:25 - 15:35 | Author(s): D. Rodríguez-Abreu
- Abstract
- Presentation
Background:
KEYNOTE-024 (ClinicalTrials.gov, NCT02142738) is a multicenter, international, phase 3, randomized, open-label, controlled trial of treatment with the anti‒PD-1 antibody pembrolizumab vs platinum-based chemotherapy as first-line therapy for patients with advanced NSCLC of any histology with PD-L1 tumor proportion score (TPS) ≥50% and without EGFR mutations or ALK translocations. Results from the primary analysis of KEYNOTE-024 demonstrated that after a median follow-up of 11.2 months, pembrolizumab significantly improved PFS (HR=0.50; P<0.001) and OS (HR=0.60; P=0.005) and was associated with a lower rate of treatment-related AEs compared with chemotherapy.
Method:
Patients were randomly assigned to receive either 35 cycles of pembrolizumab 200 mg every 3 weeks or 4–6 cycles of investigator's choice of carboplatin/cisplatin + gemcitabine, carboplatin + paclitaxel, or carboplatin/cisplatin + pemetrexed with optional pemetrexed maintenance (for those with non-squamous histology). Randomization was stratified by ECOG performance status (0 vs 1), histology (squamous vs nonsquamous), and geographic region (East Asia vs non–East Asia). Treatment continued until disease progression per RECIST version 1.1, intolerable toxicity, or withdrawal of consent. Patients in the chemotherapy arm who experienced disease progression could cross over to receive pembrolizumab monotherapy. Response was assessed every 9 weeks by blinded independent central review per RECIST version 1.1. The primary endpoint was PFS; secondary endpoints were OS, ORR, and safety.
Result:
305 patients were enrolled (pembrolizumab, n=154; chemotherapy, n=151). At the time of data cutoff (July 10, 2017) after a median follow-up of 25.2 months, 73 patients (47.4%) in the pembrolizumab arm and 96 patients (63.6%) in the chemotherapy arm had died. The hazard ratio for OS was 0.63 (95% CI, 0.47–0.86; nominal P=0.002). Median (95% CI) OS was 30.0 (18.3–not reached) months in the pembrolizumab arm and 14.2 (9.8–19.0) months in the chemotherapy arm. The Kaplan-Meier estimate of OS at 12 months was 70.3% (95% CI, 62.3%–76.9%) for the pembrolizumab group and 54.8% (95% CI, 46.4%–62.4%) for the chemotherapy group. 82 patients allocated to the chemotherapy arm crossed over to receive pembrolizumab upon meeting eligibility criteria. Treatment-related adverse events were less frequent in the pembrolizumab arm than in the chemotherapy arm (76.6% versus 90.0%, respectively) as were treatment-related grade 3-5 adverse events (31.2% versus 53.3%).
Conclusion:
With more than half of patients having OS events and prolonged follow‒up, first-line pembrolizumab monotherapy remains superior to platinum-based chemotherapy despite the crossover from the control arm to an anti-PD1 inhibitor as subsequent therapy.
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P1.07 - Immunology and Immunotherapy (ID 693)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.07-015 - Interferon-Gamma (INFG) as a Biomarker to Guide Immune Checkpoint Blockade (ICB) in Cancer Therapy (ID 8939)
09:30 - 09:30 | Author(s): D. Rodríguez-Abreu
- Abstract
Background:
PD-L1 is induced by oncogenic signals or via INFG. STAT3, through DNMT1, epigenetically silences STAT1 and RIG-I and opposes INFG signaling. TET1 is a DNA demethylase. I kappa B kinase epsilon (IKBKE), a noncanonical I-kappa-B kinase, is essential for INFG induction, but can also promote NFATc1 phosphorylation and T cell response inhibition. Eomesodermin (Eomes) regulates T cell exhaustion. CCL5 (or Rantes), dependent on STAT3, causes myeloid-derived suppressor cell (MDSC) recruitment. YAP1 can also drive MDSC recruitment via CXCL5 signaling. We have explored whether the expression of genes related to INFG signaling, T cell exhaustion and MDSC recruitment is associated with response to ICB.
Method:
Total RNA from pre-treatment tissue samples of 17 NSCLC and 21 melanoma patients treated with nivolumab and pembrolizumab respectively, was analyzed by qRT-PCR. INFG, STAT3, IKBKE, STAT1, RIG-I and PD-L1 mRNA were examined. CCL5, YAP1, CXCL5, NFATC1, EOMES and TET1 expression was additionally assessed. Gene expression was categorized with respect to tertiles and patients were divided into two risk groups (low and intermediate/high). CD8[+ ]tumor-infiltrating lymphocytes (TILs) and PD-L1 protein expression in tumor and CD8[+ ]TILs were examined by immunohistochemistry (SP57 and SP142 assay, respectively). Progression free survival (PFS), overall survival (OS) and Disease Control Rate (DCR) were estimated.
Result:
Seventeen NSCLC patients, previously treated with one or more prior systemic therapies, received nivolumab. IKBKE was positively correlated with INFG (r=0.65, p=0.0124) and PD-L1 (r=0.58, p=0.0225) expression. RIG-I was loosely anticorrelated with NFATc1 (r=-0.55, p=0.0518). Among all biomarkers explored, only INFG was associated with PFS, OS and DCR. Specifically, PFS was significantly longer for nivolumab-treated patients with intermediate/high versus low INFG expression (5.1 versus 2.0 months, p=0.0124). OS was longer (though not statistically significant) for patients with intermediate/high versus low INFG expression (10.2 versus 4.9 months, p=0.0687). DCR to nivolumab was 71.43% for patients with intermediate/high INFG versus 0% for patients with low INFG expression. Neither PD-L1 immunohistochemistry expression nor CD8[+ ]TILs were related to nivolumab outcome. The same results were observed for 21 melanoma patients treated with pembrolizumab.
Conclusion:
IFNG production by T-cells plays critical roles in anti-cancer immune responses by augmentation of MHC Class I expression, growth arrest, post-proteasomal trimming of antigen epitopes, recruitment of effector cells, induction of T-regs fragility and PD-L1 expression. Further research is warranted in order to validate whether INFG is more accurate than PD-L1.
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P2.01 - Advanced NSCLC (ID 618)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:00 - 16:00, Exhibit Hall (Hall B + C)
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P2.01-022 - Nintedanib/Docetaxel Efficacy in Advanced Lung Adenocarcinoma Treated with 1L Chemotherapy/2L Immunotherapy in Nintedanib NPU (ID 8639)
09:00 - 09:00 | Author(s): D. Rodríguez-Abreu
- Abstract
Background:
Both antiangiogenic agents (nintedanib and ramucirumab) in combination with docetaxel and monotherapy with anti-PD-1/ PD-L1 immunotherapy have demonstrated efficacy as second-line (2L) treatment of patients with stage IV lung adenocarcinoma. However, selection of optimal candidates and the most appropriate therapeutic sequence is under discussion. Herein, we report on the efficacy of the nintedanib/docetaxel combination following first-line (1L) platinum-based chemotherapy and subsequent immunotherapy in a real-world setting.
Method:
From May 2014 to December 2015, 390 patients in 108 Spanish centers enrolled in the nintedanib Named Patient Use (NPU) program. NPU inclusion criteria were advanced lung adenocarcinoma with progressive disease following at least one line of platinum-based doublet chemotherapy. We retrospectively assessed patients that received immunotherapy (available through clinical trials or the nivolumab NPU program) prior to nintedanib/docetaxel. The aim of this analysis was to evaluate the efficacy of the nintedanib/docetaxel combination in this new clinical setting.
Result:
Eleven patients met the inclusion criteria for this analysis: 64% were men; median age of 67 years (range, 44–74); ECOG performance status 0-1 in 100% of patients; median number of treatment lines before inclusion in the nintedanib NPU program was 2 (range, 2-3); PD-L1 expression was positive (unknown cut-off) in 6 patients and was not determined in 5 patients. Median progression-free survival (PFS) of first-line platinum-based chemotherapy was 3.3 months (range 1.4-9.4): 9 patients (82%) had progressed <6 months since start of first-line treatment and 4 patients (36%) had progressed <3 months. Second-line immunotherapy was pembrolizumab (36.5%), atezolizumab (36.5%) and nivolumab (27%). Median PFS of second-line immunotherapy was 2.3 months (range, 0.7-11). The overall response rate (ORR) to second-line immunotherapy was 18% with a disease-control rate (DCR) of 45%. The median number of treatment cycles of nintedanib/docetaxel was 4.5 (range, 2-22). Median PFS of nintedanib/docetaxel post first-line chemotherapy and second-line immunotherapy was 3.2 months (range, 1.4-14.6). Best response was partial response in 4 patients (36%), stable disease in 5 patients (46%), and progressive disease in 2 patients (18%), for an ORR of 36% and a DCR of 82%.
Conclusion:
Our experience in the Spanish nintedanib NPU program in patients with adenocarcinoma NSCLC pretreated with platinum-based doublet chemotherapy and immunotherapy suggests an encouraging ORR and DCR of nintedanib/docetaxel as compared with clinical trial results. These results reinforce the importance of an optimal therapeutic sequence for managing advanced lung adenocarcinoma: 1) Nintedanib/docetaxel should be the recommended second-line treatment in early progressors and 2) Possible chemosensitization effect by immunotherapy.
