Background/Purpose: 24-week data from ACT-RAY comparing an add-on strategy (tocilizumab [TCZ] + methotrexate [MTX]) with a switch strategy (TCZ + placebo [PBO]) in MTX-IR patients have been previously reported, demonstrating relevant clinical and radiographic benefit without a statistically significant difference between the 2 groups for most endpoints. Longer-term data are needed to assess the switch and add-on strategies over time and the effect of the protocol-specified treat-to-target strategy in patients who started on TCZ monotherapy or combination with MTX after Week 24. Therefore, the objective here is to assess the 52 week efficacy and safety of a TCZ-based treat-to-target strategy in patients who started treatment with and without MTX in adult patients with moderate to severe RA and an inadequate response to MTX.

Methods: ACT-RAY is a phase 3b clinical trial. Patients on stable doses of MTX were randomized to either add TCZ 8 mg/kg IV every 4 weeks to their existing MTX (add-on group) or switch to TCZ 8 mg/kg IV every 4 weeks with oral PBO (switch group). The protocol instituted the addition of open-label conventional DMARDs other than MTX at Week 24 or later in patients with DAS28 > 3.2, maintaining the blinding of MTX/PBO. 

Results: 556 patients were randomized, with 85% completing 52 weeks of treatment. Baseline data were similar between the 2 groups (disease duration 8.2 yrs, DAS28-ESR 6.3, HAQ-DI 1.47 [all mean values]) except for Genant-modified Sharp Score (GSS), which was higher in the switch group. Efficacy results are shown in the table. Between Weeks 24 and 52, the proportion of patients receiving DMARD intensification was comparable in the add-on and switch arms (29% vs 33%). Clinical improvements at Week 24 in both groups were maintained or further improved up to Week 52 with a trend in favor of the add-on strategy for some endpoints. While the vast majority of patients did not experience a change from baseline, significantly more switch patients experienced radiographic progression (14.5% versus 7.6% in the add-on group). In a preliminary analysis in patients with samples available, 3.7% of patients developed antidrug antibodies (ADAs) up to week 52: 10/272 in the add-on group and 11/271 in the switch group. Neutralizing ADAs were developed by 3.3% of patients (9/272) in the add-on group and 4.1% (11/271) in the switch group.  Rates of SAEs and serious infections per 100 PY were 14.2 and 4.9 in the add-on group and 17.7 and 6.3 in the switch group, respectively. In patients with normal baseline values, ALT elevations >3x the upper limit of normal were observed in 11% of add-on and 3% of switch patients.

Conclusion: This one year analysis suggests that TCZ monotherapy might be an acceptable therapeutic strategy in patients with a contraindication for or intolerance to MTX.

 

Table: Week 24 and 52 Efficacy Results (ITT Population)
Clinical Parameter	Week 24			Week 52
	Add-on n = 277	Switch n = 276	P value	Add-on n = 277	Switch n = 276	P value
DAS28, mean change from baseline	-3.43	-3.21	0.06a	-3.74	-3.66	0.67a
DAS28 remission (DAS28 <2.6), %	40.4	34.8	0.21	45.5	36.6	0.03
Low disease activity (DAS28 ≤3.2), %	61.7	51.4	0.031	62.5	57.2	0.12
ACR20/50/70/90,%	71.5/45.5/ 24.5/5.8	70.3/40.2/ 25.4/5.1	0.87/0.30/ 0.68/0.84	70.8/50.2/ 31.4/12.6	69.2/55.4/ 31.2/11.2	0.62/0.22/ 0.99/0.65
SJC (66)/TJC (68), mean change from baseline	−11.3/ −17.3	−11.8/ −17.0	0.8/0.9	−12.3/ −19.4	−12.2/ −18.9	0.9/0.7
GSS, mean change from baseline	0.27	0.40	0.33b	0.40	0.63	0.44b
Patients w/o radiographic progression,c %	90.6	87.3	0.18	92.4	85.5	0.007
a P values adjusted for baseline DAS28 and region.  b Estimates and Pvalues adjusted for baseline DAS28 and baseline GSS.  c No progression defined as GSS of ≤ 1.5 (SDC) (patients with missing observations classified as progressors). Not adjusted by GSS at baseline.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/clinical-radiographic-and-immunogenic-effects-after-1-year-of-tocilizumab-based-treatment-strategy-with-and-without-methotrexate-in-rheumatoid-arthritis-the-act-ray-study/