Pralatrexate Reverses the Trend to Progressive Resistance to Successive Systemic Treatment Regimens In Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma (PTCL)
Authors: O'Connor Owen A , Haouin Corinne , Zinzani Pier Luigi , Gisselbrecht Christian , Foss Francine M , Savage Kerry Joanne , Pro Barbara , Pinter-Brown Lauren , Bartlett Nancy L. , Horwitz Steven M , Jacobsen Eric D , Koutsoukos Tony , Fruchtman Steven M. , Coiffier Bertrand 
Published: October 2019

Abstract
Abstract 4881

Background:
In a wide range of malignancies, including nonHodgkin lymphoma (NHL), treatment-naive patients generally show a greater response to chemotherapy than patients receiving second-line or subsequent therapy. Furthermore, objective response rate (ORR) and progression-free survival (PFS) generally decrease with each subsequent line of therapy, the hallmark of acquired drug resistance. This trend would also be expected for PTCL, although there are no published studies or retrospective data analyses specifically in PTCL describing the pattern of response to successive treatments. The goal of the analysis presented here was to determine whether a trend of progressive resistance is observed in relapsed or refractory PTCL, and to identify the efficacy (PFS and ORR) of pralatrexate (FOLOTYN®) as a subsequent therapy relative to previous treatments. The PROPEL (Pralatrexate in Patients with Relapsed Or Refractory Peripheral T-cell Lymphoma) study is the largest data set published for relapsed or refractory PTCL to date. As a part of the patients' medical history, data were collected on response and PFS in previous lines of therapy. Patients had a median of 3 prior systemic therapies (range 1 to 12). Overall in the PROPEL study, pralatrexate demonstrated a 39% ORR by investigator assessment and a 29% ORR by central review. The median duration of response was 8.1 months by investigator assessment and 10.1 months by central review. The median duration of PFS was 4.0 months by investigator assessment and 3.5 months by central review. Median overall survival was 14.5 months.

Methods:
Analyses were conducted on patients according to the number of prior systemic therapies. PFS and ORR of the third therapy prior to pralatrexate (-3) were compared with those of the second prior therapy (-2); PFS and ORR of second prior therapy (-2) were compared with those of the last (most recent) line of therapy (-1) prior to pralatrexate; and PFS and ORR of last line of therapy (-1) were compared with pralatrexate therapy for these patients. These analyses utilized investigator assessment of PFS and response since review of tumor assessments on prior therapies was based on investigator assessment.

Results:
57 patients had undergone at least 3 prior systemic therapies before entry into PROPEL. Of these 57 patients, 34 had > 3 previous treatments and 23 had exactly 3 previous treatments. As presented in the table below, a trend of reduced PFS and ORR with successive lines of therapy was observed. The hazard ratio (HR) for outcomes worsens with successive lines of therapy [-3 vs -2: HR 0.660 (0.450, 0.967); -2 vs -1: HR 0.823 (0.566, 1.195)]. Thus, patients with ≥3 prior lines of therapy (-3) had higher response rates and PFS vs the RR and PFS in the same patients with later lines of therapy (-2 or -1).
According to this analysis, this trend was reversed with pralatrexate treatment demonstrated by a higher response rate (40%) and longer PFS (median =134 days) than the previous line of therapy. The only HR >1 in this analysis, indicating a longer PFS for a more recent line of therapy vs the most recent prior line of therapy, is for pralatrexate vs -1. The same analyses were performed on the 86 patients who had undergone at least 2 previous treatments. The trend for PFS and response rate to decrease with each subsequent treatment was again demonstrated and was again reversed with pralatrexate (HR for PFS = 1.201 [-1 vs -0] vs 0.785 [-2 vs -1]).

Conclusions:
This is the first analysis to demonstrate that patients with PTCL exhibit the same pattern of progressive resistance as seen in most other tumor types. It is also the first to demonstrate that a drug, pralatrexate, can reverse the pattern of progressive resistance in patients with drug-resistant PTCL. Pralatrexate demonstrated higher responses and longer PFS than would be expected in a later line of therapy setting, thus reversing the trend of progressive resistance.

Disclosures:
O'Connor: Allos Therapeutics, Inc.: Research Funding. Haouin: GlaxoSmithKline: Consultancy; Amgen Inc.: Consultancy. Gisselbrecht: Allos Therapeutics, Inc.: Research Funding. Foss: Allos Therapeutics, Inc.: Consultancy, Speaker. Savage: Allos Therapeutics, Inc.: Consultancy, Honoraria. Pro: Allos Therapeutics, Inc.: Research Funding. Pinter-Brown: Allos Therapeutics, Inc.: Consultancy. Horwitz: Allos Therapeutics, Inc.: Consultancy, Research Funding. Jacobsen: Allos Therapeutics, Inc.: Consultancy. Koutsoukos: Allos Therapeutics, Inc.: Employment. Fruchtman: Allos Therapeutics, Inc.: Employment.