ORLANDO, Fla. — Treatment with ibrutinib prolonged PFS and led to a significantly higher overall response rate compared with temsirolimus in previously treated patients with mantle cell lymphoma, according to phase 3 study results presented at the ASH Annual Meeting and Exposition.
“Mantle cell lymphoma is a rare but aggressive disease,” Simon Rule, MD, head of lymphoma service at Derrifield Hospital and senior lecturer at Plymouth University Peninsulas School of Medicine and Dentistry in England, said during a presentation. “Most patients progress after first-line therapy, with a median OS of around 1 to 2 years.”
The oral Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica; Janssen, Pharmacyclics) appeared highly active in previously treated patients (ORR = 65%; complete response = 20%) in single-arm phase 2 studies. Thus, Rule and colleagues conducted a randomized, open-label phase 3 study comparing ibrutinib with temsirolimus (Torisel, Pfizer) in 280 patients (median age, 68 years; range, 34-88), with relapsed or refractory mantle cell lymphoma. Patients had received a median of two prior lines of therapy (range, 1-9).
The researchers randomly assigned 139 patients to 560 mg daily ibrutinib and 141 patients to IV temsirolimus (175 mg on days 1, 8 and 15 of first cycle; 75 mg on days 1, 8 and 15 of subsequent cycles) until disease progression or unacceptable toxicity.
PFS served as the primary endpoint. Overall response rate (ORR), OS time to next treatment, time to worsening of symptoms and safety served as secondary endpoints.
Median follow-up was 20 months.
Median PFS was 14.6 months in the ibrutinib arm vs. 6.2 months in the temsirolimus arm. Thus, ibrutinib conferred a 57% reduction in the risk for progression or death compared with temsirolimus (HR = 0.43; 95% CI, 0.32-0.58).
Further, more patients assigned ibrutinib achieved 2-year PFS (41% vs. 7%). Rule noted that the investigator-reported and independently confirmed PFS rates were identical.
The ORR also was significantly higher in the ibrutinib arm (71.9% vs. 40.4%; P < .0001). The complete response rate was 18.7% for ibrutinib and 1.4% for temsirolimus.
Median OS showed a positive trend in favor or ibrutinib (median, not reached vs. 21.3 months). Ibrutinib reduced risk for death 24% (HR = 0.76; 95% CI, 0.53-1.09).
However, the researchers acknowledged that these results may be confounded because 23% of patients originally assigned temsirolimus crossed over to ibrutinib.
A greater number of patients in the ibrutinib arm avoided worsening of lymphoma symptoms (27% vs. 52%). Median time to next treatment was not reached for ibrutinib vs. 11.6 months for temsirolimus.
Patients assigned ibrutinib had a longer median treatment duration (14.4 months vs. 3 months). Further, fewer patients in the ibrutinib arm discontinued treatment due to adverse events (12.9% vs. 29.5%).
The most commonly reported treatment-emergent adverse events associated with ibrutinib included diarrhea, fatigue and cough. Adverse events associated with temsirolimus included thrombocytopenia, anemia and diarrhea.
Grade 3 treatment-emergent adverse events — including thrombocytopenia, anemia and neutropenia — occurred in 67.6% of patients assigned ibrutinib and 87.1% of patients assigned temsirolimus.
Six patients assigned ibrutinib and three patients assigned temsirolimus experienced atrial fibrillation. However, no patients discontinued treatment due to its emergence.
Further, 3.6% of patients in the ibrutinib arm and 2.9% of patients in the temsirolimus arm developed secondary malignancies. According to rule, these mostly comprised nonmelanoma skin cancers.
“Our study provides further evidence that ibrutinib should be considered the treatment of choice for patients with previously treated mantle cell lymphoma,” Rule said. – by Cameron Kelsall
Rule S, et al. Abstract 469. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.
Disclosure: Rule reports research funding and travel expenses from and consultant roles with Celgene, Gilead, Johnson & Johnson, and Roche. Please see abstract for a list of all other researchers’ relevant financial disclosures.