San Diego, California—Ibrutinib administered in combination with rituximab demonstrated continued superiority over rituximab alone in patients with Waldenström Macroglobulinemia (WM), according to follow-up safety and efficacy results from the iNNOVATE clinical trial.

These findings were presented by Christian Buske, MD, Comprehensive Cancer Center Ulm, Institute of Experimental Cancer Research, University Hospital of Ulm, Germany, at the 2018 ASH Annual Meeting.

The iNNOVATE Clinical Trial

The phase 3 iNNOVATE study enrolled patients with confirmed, symptomatic WM requiring therapy.

In the randomized portion of the trial (arms A and B), patients previously treated with rituximab were required to have had at least a major response to their last rituximab-based regimen. These patients were randomized to receive rituximab 375 mg/m2 weekly with ibrutinib 420 mg daily or placebo. In arm C of the trial, patients who did not achieve a major response or whose disease relapsed within 12 months of their last rituximab-containing therapy received ibrutinib 420 mg daily until progressive disease or unacceptable toxicity occurred.

The end points of the study included progression-free survival (PFS), response rates, overall survival (OS), hemoglobin improvement, time to next treatment, patient-reported outcomes (PROs), and safety.

A total of 150 patients were randomized to arms A (n = 75) and B (n = 75); 45% of these patients were treatment-naïve.

With prolonged follow-up and median treatment durations of 29.5 months with ibrutinib plus rituximab and 15.5 months with rituximab alone, major response rates were 77% versus 33%, respectively. The overall response rates were 95% versus 48%, respectively. With continued treatment with ibrutinib plus rituximab, 27% of patients achieved a very good partial response compared with 3% who received rituximab alone.

Results in Arms A and B

The median PFS was not reached in the combination arm and was 20.3 months with rituximab alone. The estimated 30-month PFS and OS was 79% versus 41% and 93% versus 90%, respectively.

A total of 31 patients in the monotherapy arm crossed over to the ibrutinib plus rituximab arm after their disease progressed. Treatment with ibrutinib plus rituximab was ongoing in 73% of patients. The most common reasons for discontinuation of ibrutinib were disease progression (9%) and withdrawal of patient consent (9%).

The safety profile of ibrutinib and rituximab was consistent with previous reports. Overall, adverse events of grade ≥3 occurred in 61% of patients; 53% of these events occurred in the first 12 months of treatment, and the remaining 8% with longer follow-up.

Serious adverse events occurred in 43% of patients receiving ibrutinib plus rituximab versus 33% of patients receiving rituximab alone. Similarly, the incidence of serious adverse events was 39% in the first 12 months of treatment, and increased by 4% with longer follow-up.

Results in Arm C

In arm C, 31 patients received single-agent ibrutinib; 71% of them had undergone ≥3 previous therapies. All patients in this arm were refractory to rituximab, and 90% had previously received cyclophosphamide.

With longer follow-up, PFS was not reached, and the 36-month PFS was estimated at 61%. The major response rate was 77% and overall response rate was 90%, with an estimated 36-month OS of 84%. Improved hemoglobin levels were seen in 71% of patients. Treatment was ongoing in 52% of patients.

The median duration of ibrutinib treatment was 37 months, with no major hemorrhagic or atrial fibrillation events reported. Adverse events of grade ≥3 occurred in 74% of patients, and 39% had serious adverse events. No treatment-related deaths were reported.

Combination Superior to Monotherapy

“IR [ibrutinib plus rituximab] showed continued superiority over R [rituximab], in treatment-naïve and previously treated patients with WM, regardless of genotypic factors. Similarly, in heavily pretreated, rituximab-refractory pts with follow-up >3 years, single-agent ibrutinib was highly active and response improved over time,” Dr Buske and colleagues said.

“Alone or in combination, ibrutinib had a manageable safety profile and no new safety signals were identified with longer follow-up,” they concluded.—Janelle Bradley

Buske C, Tedeschi A, Trotman J, et al. Ibrutinib treatment in Waldenström’s Macroglobulinemia: follow-up efficacy and safety from the iNNOVATE study. Presented at: the 60th ASH Annual Meeting and Exposition; December 1-4, 2018; San Diego, CA. Abstract 149.