Dolled‐Filhart, Marisa

8072 Background: Figitumumab (CP-751,871) is a fully human, IgG2monoclonal antibody against the insulin-like growth factor type I receptor (IGF-IR). We reported in a randomized phase II study (ASCO 2008), preliminary evidence of high activity of the combination of paclitaxel (T), carboplatin (C) and figitumumab (F) in advanced treatment-naïve NSCLC of squamous cell histology (n=11 pts). A single arm trial extension cohort was conducted to confirm those findings. Methods: Fifty-six pts with non-adenocarcinoma NSCLC were enrolled. Pts received T (200 mg/m2), C (AUC of 6) and F (20 mg/kg) q3weeks for up to 6 cycles; pts with response (PR) or stable disease were eligible to continue F as single agent until disease progression. Statistical hypotheses were 30% (null) versus 50% (response of interest). Protein expression of the IGF-IR in core tumor biopsies was quantified using automated quantitative analysis (AQUA) technology. Results: Pts were 72% male, 28% >70 years old and 91% stage IV. Median number of treatment cycles was 4, with 46% of pts receiving single agent F beyond cycle 4. TCF was well tolerated. The most common all-causality grade 3, 4 CTCAE adverse events were neutropenia (21%), hyperglycemia (14%) and fatigue (14%). Hyperglycemia adverse events almost always occurred within the first treatment cycle and were manageable with standard measures. Responses in squamous pts are currently 25 out of 40 pts according to RECIST, with final response assessment still pending for 7 additional pts (≥53%, p<0.001). One complete response and 7 striking PRs (50–80% tumor size reduction at cycle 2) were observed. Tumor size reductions with F maintenance treatment were also seen in 2 pts. Median progression free survival has not been yet reached at 4 months follow up. A trend (p=0.1) for higher IGF-IR expression in patients responding to TCF was observed in a small data set (n=12). Median tumor IGF-IR expression in pts responding to TCF therapy and non-responders were respectively 6287 and 4131 AQUA scores. Analysis of IGF-IR and other members of the IGF-IR pathway continues. Conclusions: These data further support the activity of figitumumab combination therapy in pts with squamous NSCLC. [Table: see text]

Abstract Background: Previous data on the relationship between PD-L1 expression and activity of anti-PD-1 and anti-PD-L1 antibodies have been conflicting. MK-3475, a humanized monoclonal IgG4 antibody against PD-1, has demonstrated durable antitumor activity in MEL and NSCLC. We evaluated tumor PD-L1 expression and its relationship with outcomes in a phase I clinical trial of MK-3475. We also evaluated T cell activation as a pharmacodynamic marker of MK-3475 activity. Methods: 135 MEL pts received MK-3475 10 mg/kg Q2W, 10 mg/kg Q3W, or 2 mg/kg Q3W. Tumor response was assessed by RECIST 1.1 per independent central review, including requirement for a confirmatory CT scan. Pretreatment biopsy was required. Serial blood samples were collected before infusion at the start of cycles 1-5 (Q2W dosing) or 1-4 (Q3W dosing). Tumor PD-L1 expression was assessed by IHC. A preliminary cutoff of 1% of stained cells was used to define PD-L1 positivity. Absolute CD4+ and CD8+ T cell counts and the percentage of activated (HLA-DR as marker) CD4+ and CD8+ T cells in peripheral blood were assessed by multiplex flow cytometry (n = 101). Results: Median PFS was 36 weeks, 6-month overall survival (OS) rate was 89%, and 12-month OS rate was 81%. Median duration of response and OS were not reached. In the 116 pts with measurable disease, ORR was 41%. PFS and response rate were significantly associated with tumor PD-L1 expression (Table). At week 6, a statistically significant percent increase from baseline in the percentage of activated (HLA-DR+) CD4+ and CD8+ T cells was observed at all doses (pooled mean percent change [SE], +24.0% [4.7%] for HLA-DR+/CD8+, +17.5% [2.7%] for HLA-DR+/CD4+). Conclusions: Tumor PD-L1 expression levels were associated with tumor response and PFS in MEL pts treated with MK-3475; activity was also observed in pts with low PD-L1 expression. As assessed by HLA-DR expression, post-treatment T cell activation in the circulating pool was increased at all doses tested. Patients WithMeasurable Disease and Interpretable PD-L1 IHC ResultsPatients With InterpretablePD-L1 IHC Results and PFS and OS Data PD-L1 TumorExpressionNORR, n (%)NPFS at 6 months, % (95% CI)Median PFSOS at 6 months, % (95% CI)Median OSPositive (membrane staining in ≥1% of cells)5529 (53)6058 (47-72)10.6 mo93(87-100)Not reachedNegative (membrane staining in &lt;1% of cells)161* (6)2232 (16-64)2.9 mo75(58-97)Not reachedHR (95% CI) for PD-L1-positive vs negative____0.54(0.28-1.05)_0.67(0.25-1.83)One-sidedP value(PD-L1 association test)_&lt;0.004 (logistic regression)__0.034(Cox regression)_0.220(Cox regression)*IPI-pretreated patient who received MK-3475 10 mg/kg Q2W. Citation Format: Adil I. Daud, Omid Hamid, Antoni Ribas, F. Stephen Hodi, Wen-Jen Hwu, Richard Kefford, Jedd Wolchok, Peter Hersey, Jeffrey S. Weber, Richard Joseph, Tara C. Gangadhar, Roxana S. Dronca, Amita Patnaik, Hassane Zarour, Anthony M. Joshua, Kevin Gergich, Dianna Wu, Jared K. Lunceford, Kenneth Emancipator, Marisa Dolled-Filhart, Nicole Li, Scot Ebbinghaus, S. Peter Kang, Caroline Robert. Antitumor activity of the anti-PD-1 monoclonal antibody MK-3475 in melanoma(MEL): Correlation of tumor PD-L1 expression with outcome. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT104. doi:10.1158/1538-7445.AM2014-CT104