Background-Phase 3 clinical data has shown higher proportions of patients with objective response, longer response duration, and longer overall survival with nivolumab versus docetaxel in patients with previously treated advanced non-small-cell lung cancer (NSCLC). We aimed to evaluate the long-term benefit of nivolumab and the effect of response and disease control on subsequent survival. Methods-We pooled data from four clinical studies of nivolumab in patients with previously treated NSCLC (CheckMate 017, 057, 063, and 003) to evaluate survival outcomes. Trials of nivolumab in the second-line or later setting with at least 4 years follow-up were included. Comparisons of nivolumab versus docetaxel included all randomised patients from the phase 3 CheckMate 017 and 057 studies. We did landmark analyses by response status at 6 months to determine post-landmark survival outcomes. We excluded patients who did not have a radiographic tumour assessment at 6 months. Safety analyses included all patients who received at least one dose of nivolumab. Findings-Across all four studies, 4-year overall survival with nivolumab was 14% (95% CI 11-17) for all patients (n=664), 19% (15-24) for those with at least 1% PD-L1 expression, and 11% (7-16) for those with less than 1% PD-L1 expression. In CheckMate 017 and 057, 4-year overall survival was 14% (95% CI 11-18) in patients treated with nivolumab, compared with 5% (3-7) in patients treated with docetaxel. Survival subsequent to response at 6 months on nivolumab or docetaxel was longer than after progressive disease at 6 months, with hazard ratios for overall survival of 0•18 (95% 0•12-0•27) for nivolumab and 0•43 (0•29-0•65) for docetaxel; for stable disease versus progressive disease, hazard ratios were 0•52 (0•37-0•71) for nivolumab and 0•80 (0•61-1•04) for docetaxel. Long-term data did not show any new safety signals. Interpretation-Patients with advanced NSCLC treated with nivolumab achieved a greater duration of response compared with patients treated with docetaxel, which was associated with a long-term survival advantage. Funding-Bristol-Myers Squibb.
9005 Background: MET exon 14 skipping ( METex14) mutations - reported in 3~4% of NSCLC patients (pts) - are activating, sensitive to MET inhibition and can be conveniently detected using liquid biopsy (LBx). We report data from an ongoing single-arm phase II study of tepotinib, a highly selective MET inhibitor, in NSCLC pts with METex14 mutations identified by LBx or tumor biopsy (TBx) (NCT02864992). Methods: Pts with advanced WT EGFR/ALK NSCLC, prospectively enrolled via either LBx (≥60 pts) or TBx (≥60 pts, overlap anticipated) central RNA-based METex14 mutation testing, receive tepotinib 500 mg QD until progression, intolerable toxicity or withdrawal. Primary endpoint: objective response rate (ORR) by independent review (IRC). Secondary endpoints: ORR by investigator assessment (INV) and safety. Results: To date, 85 pts have been enrolled (55 LBx pts and 52 TBx pts). At data cut-off (16 Oct 2018), in 35 evaluable LBx pts (≥2 post-baseline assessments or discontinuation for any reason), ORR was 51.4% by IRC and 63.9% by INV. In 41 evaluable TBx pts, ORR was 41.5% by IRC and 58.5% by INV. Median duration of response (mDoR) and ORR by line of treatment are shown in the table. Any grade treatment-related adverse events (TRAEs) reported by ≥10% of 69 pts evaluable for safety were peripheral edema (47.8%), diarrhea (18.8%), nausea (15.9%), asthenia (10.1%). No TRAEs were grade 4 or led to death. TRAEs led to permanent discontinuation in 2 (2.9%) pts (1 ILD, 1 diarrhea & nausea). Conclusions: Tepotinib has promising activity with a long DoR across treatment lines in NSCLC pts with METex14 mutations detected by LBx or TBx. The safety profile was favorable. Recruitment is ongoing. Clinical trial information: NCT02864992. [Table: see text]
Although many cancers initially respond to cisplatin (CDDP)-based chemotherapy, resistance frequently develops. Insulin-like growth factor-binding protein-3 (IGFBP-3) silencing by promoter methylation is involved in the CDDP-acquired resistance process in non-small cell lung cancer (NSCLC) patients. Our purpose is to design a translational-based profile to predict resistance in NSCLC by studying the role of IGFBP-3 in the phosphatidyl inositol 3-kinase (PI3K) signaling pathway. We have first examined the relationship between IGFBP-3 expression regulated by promoter methylation and activation of the epidermal growth factor receptor (EGFR), insulin-like growth factor-I receptor (IGFIR) and PI3K/AKT pathways in 10 human cancer cell lines and 25 NSCLC patients with known IGFBP-3 methylation status and response to CDDP. Then, to provide a helpful tool that enables clinicians to identify patients with a potential response to CDDP, we have calculated the association between our diagnostic test and the true outcome of analyzed samples in terms of cisplatin IC50; the inhibitory concentration that kills 50% of the cell population. Our results suggest that loss of IGFBP-3 expression by promoter methylation in tumor cells treated with CDDP may activate the PI3K/AKT pathway through the specific derepression of IGFIR signaling, inducing resistance to CDDP. This study also provides a predictive test for clinical practice with an accuracy and precision of 0.84 and 0.9, respectively, (P=0.0062). We present a biomarker test that could provide clinicians with a robust tool with which to decide on the use of CDDP, improving patient clinical outcomes.
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