Efficacy and safety of ocrelizumab in patients with relapsing‐remitting multiple sclerosis with suboptimal response to prior disease‐modifying therapies: A primary analysis from the phase 3b CASTING single‐arm, open‐label trial

Abstract

Background and purpose Using the treatment goal of “no evidence of disease activity” (NEDA) incorporating magnetic resonance imaging (MRI) re‐baselining, we aimed to assess the efficacy of ocrelizumab in patients with relapsing‐remitting multiple sclerosis with a prior suboptimal response, defined by MRI or relapse criteria, to one or two disease‐modifying therapies (DMTs). Methods CASTING was a prospective, international, multicenter, single‐arm, open‐label phase 3 trial (NCT02861014). Patients (Expanded Disability Status Scale [EDSS] score ≤ 4.0, with discontinued prior DMT of ≥6 months duration due to suboptimal disease control) received intravenous ocrelizumab 600 mg every 24 weeks for 96 weeks. The primary endpoint was NEDA (defined as absence of relapses, disability progression, and inflammatory MRI measures, with prespecified MRI re‐baselining at Week 8) over 96 weeks. Results A total of 680 patients were enrolled, 167 (24.6%) based on MRI activity only. At Week 96, 74.8% (95% confidence interval [CI] 71.3–78.0, n/N = 492/658) of patients had NEDA. NEDA was highest among patients enrolled due to MRI activity alone (80.6% [95% CI 68.6–89.6], n/N = 50/62) versus those enrolled for relapse (75.1% [95% CI 69.0–80.6], n/N = 172/229) or for relapse with MRI (70.5% [95% CI 60.0–79.0], n/N = 74/105). NEDA across subgroups was highest in patients with a baseline EDSS score <2.5 (77.2% [95% CI 72.8–81.2], n/N = 315/408). NEDA was higher in patients receiving one prior DMT (77.6% [95% CI 73.2–81.6], n/N = 312/402) versus two prior DMTs (70.3% [95% CI 64.3–75.8], n/N = 180/256). Conclusions In patients switching therapy due to suboptimal disease control, treatment with ocrelizumab led to an overall high NEDA rate across a wide range of disease‐related and demographic subgroups, regardless of prior treatment background, with no new safety signals detected.

Ocrelizumab: A Review in Multiple Sclerosis

“…2.1.2 ) [ 11 ], in addition to interim data from ongoing phase IIIb or IV trials in patients with treatment-naïve, early stage RRMS (ENSEMBLE [ 12 ]) and RMS previously treated with natalizumab (ENCORE [ 13 ]). The specific efficacy of ocrelizumab in patients with RRMS and a suboptimal response to prior DMTs has been investigated in two open-label, single-arm, multicentre phase IIIb studies (CHORDS in North America [ 14 ] and CASTING in the EU [ 15 ]; Sect. 2.1.3 ).…”

“…CASTING [ 15 ] and CHORDS [ 14 ] enrolled patients aged 18–55 years with a diagnosis of RRMS (based on the 2010 revised McDonald criteria), a disease duration from first symptom of < 10 years [ 15 ] or ≤ 12 years [ 14 ] and a screening EDSS score of 0.0–4.0 [ 15 ] or 0.0–5.5 [ 14 ]. Eligible patients had received ≤ 2 [ 15 ] or ≤ 3 [ 14 ] other DMTs prior to screening and had discontinued the most recent adequately used DMT due to suboptimal disease control [ 14 , 15 ].…”

“…CASTING [ 15 ] and CHORDS [ 14 ] enrolled patients aged 18–55 years with a diagnosis of RRMS (based on the 2010 revised McDonald criteria), a disease duration from first symptom of < 10 years [ 15 ] or ≤ 12 years [ 14 ] and a screening EDSS score of 0.0–4.0 [ 15 ] or 0.0–5.5 [ 14 ]. Eligible patients had received ≤ 2 [ 15 ] or ≤ 3 [ 14 ] other DMTs prior to screening and had discontinued the most recent adequately used DMT due to suboptimal disease control [ 14 , 15 ]. In both trials, patients received ocrelizumab 600 mg (administered as two 300 mg infusions on days 1 and 15 for the initial dose and a single 600 mg infusion thereafter) every 24 weeks for 96 weeks ( n = 680 evaluated in CASTING and 576 in CHORDS).…”

“…In both trials, patients received ocrelizumab 600 mg (administered as two 300 mg infusions on days 1 and 15 for the initial dose and a single 600 mg infusion thereafter) every 24 weeks for 96 weeks ( n = 680 evaluated in CASTING and 576 in CHORDS). The primary endpoint was NEDA (with prespecified MRI re-baselining at week 8 [ 15 ]), defined as the absence of 24-week CDP, protocol-defined relapse, gadolinium-enhancing T 1 lesions and new or enlarging T 2 lesions, over 96 weeks [ 14 , 15 ].…”

“…The proportion of ocrelizumab recipients with NEDA over 96 weeks was 48.1% in CHORDS [ 14 ] and 74.8% (with MRI re-baselining at week 8) in CASTING [ 15 ]. Most patients were free from 24-week CDP (89.6% in CHORDS and 87.5% in CASTING), protocol-defined relapses (89.6% and 89.8%), gadolinium-enhancing T 1 lesions (95.5% and 97.7%) and new or enlarging T 2 lesions (59.5% and 91.5%) [ 14 , 15 ].…”