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Mogamulizumab vs. investigator's choice in ATL
(Independent Review) and by the investigators (Investigator Assessment). Response, stringently and globally evaluated in six potential disease compartments (blood, skin, lymph nodes, extra- nodal masses, liver/spleen, and bone marrow), was determined according to published response criteria for ATL25 that assessed skin via modified Severity Weighted Assessment Tool; lymph nodes, extranodal masses, liver, and spleen by PET and/or CT; and bone marrow by biopsy at baseline and to confirm PD or CR; cen- tral flow cytometry rather than morphology was used for blood evaluation. Response was determined at the end of the first treat- ment cycle and every 8 weeks thereafter. cORR required confir- mation and maintenance of response at the next successive evalu- ation. Best response included all responses at any time point. PFS, OS, time to response, and DoR were defined according to stan- dard methods.
Adverse events (AEs) were coded by Medical Dictionary for Regulatory Activities, v.15.0 and graded using the National Cancer Institute Common Terminology Criteria v.4.0. For patients receiv- ing mogamulizumab who developed a grade 2 or greater skin rash, treatment was to be interrupted and the rash treated with topical steroids.
Validated electrochemiluminscence immunoassays were used to determine anti-mogamulizumab and neutralizing anti-moga- mulizumab antibodies. Correlative studies were done to study mogamulizumab pharmacokinetics and neutralizing antibody. CCR4 expression status was determined by flow cytometry in patients with blood disease (CD45+CD4+CD25+CCR4+CD7– ≥5% considered positive) or by immunohistochemistry (positive value defined as ≥10%) in those without blood involvement.
Statistical analysis
The sample size was estimated based on a feasible accrual of approximately 70 patients, which was predicted to require 3 years. The primary end point, cORR by Independent Review, was estimated using an exact 95% confidence interval (CI). The moga- mulizumab arm sample size (n=47) was chosen to yield a maxi- mum width of a 95%CI on ORR to be <30%. This does not assume a target value for ORR due to the rarity of ATL and the lack of published efficacy data for the investigator’s choice options in the relapsed and refractory setting. With 2:1 randomization approximately 23 patients would be enrolled in the investigator’s choice arm.
All analyses were performed using SAS v.9.3 (SAS Institute, Cary, NC, USA). Comparison of cORR between treatment arms was performed using an exact 95% unconditional confidence for the risk difference. Survival estimates were calculated using the Kaplan-Meier method. PFS and OS were analyzed using Cox pro- portional hazards models, and, if data warranted, for PFS using a multivariate Cox proportional model adjusting for selected poten- tial prognostic factors. Other results are shown descriptively.
Results
Patients
A total of 71 patients were enrolled to the moga- mulizumab (n=47) and investigator’s choice (n=24) arms between August 2012 and May 2015 (Figure 1). Two patients, both in the mogamulizumab arm, remained on treatment at time of efficacy data cut-off on March 31, 2016. A final data cut-off for survival data was made on December 31, 2017. Investigator’s choice regimens were GemOx (n=21), pralatrexate (n=2), and DHAP (n=1). All 71 randomized patients were included in the intent-to- treat (ITT) and safety populations. Eighteen of the 24
patients (75%) from the investigator’s choice arm crossed over to receive mogamulizumab as administered in the randomized study.
Characteristics of the randomized patients are shown in Table 1. Despite randomization, there were imbalances between the treatment arms in known prognostic fac- tors.15 The mogamulizumab arm had a higher median age (55.0 vs. 50.5 years), with a consequently higher propor- tion of patients aged >65 years (23% vs. 4%) and fewer aged <40 years (13% vs. 29%) compared to the investiga- tor’s choice arm. More patients had an ECOG perform- ance status of 2 in the mogamulizumab arm (40% vs. 29%). In addition, patients randomized to investigator’s choice of chemotherapy were more likely to have been responsive to their most immediate prior therapy versus those randomized to mogamulizumab (46% vs. 26%, respectively) and were less likely to have bone marrow involvement (33% vs. 57%). The treatment arms were well balanced with respect to other characteristics includ- ing gender, geographical region, ATL subtype, and prior ATL regimens. Tumor CCR4-positivity was 96% in each arm.
Despite amending the protocol to enroll patients less heavily pre-treated and more likely to benefit, the number of patients with ECOG performance status of 2 and those responding to immediate prior therapy was virtually the same pre- and post-amendment (Online Supplementary Table S1). Furthermore, the percentage of patients who completed ≤1 cycle was the same pre- and post-amend- ment (65% for both), indicative of the aggressive nature of their disease. These patients were considered non-respon- ders in the ITT analysis.
Efficacy
Confirmed ORR by Independent Review for moga- mulizumab was 11% [1 complete response (CR), 4 partial response (PR); 95%CI: 4-23%] compared to 0% (95%CI: 0-14%) for the investigator’s choice arm. Best response was 28% (95%CI: 16-43%) versus 8% (95%CI: 1-27%) for mogamulizumab and investigator’s choice, respectively. A secondary analysis comparing cORR by treatment as assessed by Independent Review did not detect a signifi- cant difference (risk difference 10.6%; 95%CI: –14%- 34%).
By Investigator Assessment, cORR was 15% (95%CI: 6-28%) for mogamulizumab compared to 0% (95%CI: 0-14%) for the investigator’s choice arm. Best response was 34% (95%CI: 21-49%) versus 0% (95%CI: 0-14%) (Table 2), respectively.
Independent and investigator review identified a largely concordant group of responding patients, suggesting response assessment was not influenced by investigator bias. Because Investigator Assessments were considered to provide a more comprehensive evaluation of the patients' disease status and potential clinical improvement (investigators had access to all local labs, physical exam findings, and skin rash/infusion reaction, which was with- held from independent review to preserve blind condi- tions), the following, secondary efficacy results are described based upon Investigator Assessment only.
By compartment responses to mogamulizumab (Table 2 and Online Supplementary Table S3) were highest in blood (21/39; 54%, all CR) and skin (8/18; 44%). Responses by compartment to investigator’s choice of chemotherapy were only seen in skin (5/9, 56%) and blood (1/18, 6%). In
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