Presentation Abstract

Abstract Number: CT104
Presentation Title: Antitumor activity of the anti-PD-1 monoclonal antibody MK-3475 in melanoma(MEL): Correlation of tumor PD-L1 expression with outcome
Presentation Time: Sunday, Apr 06, 2014, 4:15 PM - 4:35 PM
Location: Ballroom 20A-C, San Diego Convention Center
Author Block: Adil I. Daud1, Omid Hamid2, Antoni Ribas3, F. Stephen Hodi4, Wen-Jen Hwu5, Richard Kefford6, Jedd Wolchok7, Peter Hersey6, Jeffrey S. Weber8, Richard Joseph9, Tara C. Gangadhar10, Roxana S. Dronca11, Amita Patnaik12, Hassane Zarour13, Anthony M. Joshua14, Kevin Gergich15, Dianna Wu15, Jared K. Lunceford16, Kenneth Emancipator16, Marisa Dolled-Filhart16, Nicole Li15, Scot Ebbinghaus15, S. Peter Kang17, Caroline Robert18. 1UCSF School of Medicine, San Francisco, CA; 2The Angeles Clinic and Research Institute, Los Angeles, CA; 3David Geffen UCLA School of Medicine, Los Angeles, CA; 4Dana-Farber Cancer Institute, Boston, MA; 5The University of Texas MD Anderson Cancer Center, Houston, TX; 6University of Sydney, Sydney, Australia; 7Memorial Sloan-Kettering Cancer Center, New York, NY; 8H. Lee Moffitt Cancer Center, Tampa, FL; 9Mayo Clinic Cancer Center, Jacksonville, FL; 10Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA; 11Mayo Clinic, Rochester, MN; 12South Texas Accelerated Research Therapeutics (START), San Antonio, TX; 13University of Pittsburgh, Pittsburgh, PA; 14Princess Margaret Cancer Centre, Toronto, ON, Canada; 15Merck, North Wales, PA; 16Merck, Rahway, NJ; 17Merck Research Laboratories, Kenilworth, NJ; 18Gustave Roussy, Villejuif, France
Abstract Body: 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 With
Measurable Disease and Interpretable PD-L1 IHC Results
PD-L1 Tumor
Expression
NORR, n (%)NPFS at 6 months, % (95% CI)Median PFSOS at 6 months, % (95% CI)Median OS
Positive (membrane staining in ≥1% of cells)5529 (53)6058 (47-72)10.6 mo93
(87-100)
Not reached
Negative (membrane staining in <1% of cells)161* (6)2232 (16-64)2.9 mo75
(58-97)
Not reached
HR (95% CI) for PD-L1-positive vs negative____0.54
(0.28-1.05)
_0.67
(0.25-1.83)
One-sided
P value
(PD-L1 association test)
_<0.004 (logistic regression)__0.034
(Cox regression)
_0.220
(Cox regression)
*IPI-pretreated patient who received MK-3475 10 mg/kg Q2W.