The FDA expanded the indication of ibrutinib (Imbruvica) to include its combination with rituximab (Rituxan) for the initial treatment of adult patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).1
The review was conducted under Project Orbis, and the FDA is collaborating with the Australian Therapeutic Goods Administration, Health Canada, and Swissmedic as they continue to review the application.
The approval was based on the phase III E1912 trial, which was a multicenter, open-label, activity-controlled trial which randomized patients in a 2:1 fashion to either ibrutinib with rituximab or a combination of fludarabine (Fludara), cyclophosphamide, and rituximab (FCR). The primary endpoint for the trial was progression-free survival (PFS), and one of the secondary endpoints was overall survival (OS).2
The primary study results were published in The New England Journal of Medicine, and the extended 4-year median follow-up results were presented at the 2019 American Society of Hematology (ASH) Annual Meeting.
“The gold-standard first-line treatment option for many patients with chronic lymphocytic leukemia who were fit enough to tolerate an aggressive treatment course had been the intravenous chemoimmunotherapy of FCR – that is, until today,” Brian Koffman, MD, CM, chief medical officer and executive vice president of the CLL Society, a nonprofit organization focused on CLL patient education, support and research, said in a press release.3
“The FDA approval of ibrutinib and rituximab regimen is welcome news for these previously untreated patients who have been looking forward to a non-chemotherapy treatment option,” Koffman added. “The results from ECOG-ACRIN's E1912 clinical trial in previously untreated, younger adult patients and today's milestone represent a paradigm shift in how physicians can treat patients with CLL and may enable many to choose a non-chemotherapy treatment option.”
Researchers assessed a total 529 adult patients (354 on ibrutinib-rituximab, 175 on FCR) 70 years or younger with previously treated CLL or SLL requiring systemic therapy. Patients with 17P deletion were excluded from the study. Further, ibrutinib was administered daily at a dose of 420 mg until disease progression or unacceptable toxicity. Rituximab was initiated in cycle 2 and administered at 50 mg/m2 on day 1, 325 mg/m2 on day 2, and 500 mg/m2 on day 1 of 3 subsequent cycles, for a total of 7 cycles; each cycle was 28 days.
A statistically significant improvement in PFS was observed in patients receiving ibrutinib plus rituximab compared with those receiving FCR (89.4% vs. 72.9% at 3 years; hazard ratio [HR], 0.35; 95% CI, 0.22-0.56; P < 0.001). However, median PFS was not reached in either arm after a median follow-up duration of 37 months.
The results of the analysis of OS also favored ibrutinib-rituximab over FCR (98.8% vs. 91.5% at 3 years; HR, 0.17; 95% CI, 0.05-0.54; P < 0.001).
The incidence of adverse events of grade 3 or higher was found to be similar in the 2 groups (in 282 of 352 patients [80.1%] who received ibrutinib-rituximab and in 126 of 158 [79.7%] who received FCR), while infectious complications of grade 3 or higher were less common with ibrutinib–rituximab than with chemoimmunotherapy (in 37 patients [10.5%] vs. 32 [20.3%], P < 0.001). The most common adverse reactions (≥30%) observed in patients with CLL/SLL receiving ibrutinib are thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, bruising, and nausea.
“FCR, a chemoimmunotherapy-based regimen, has been the standard of care for many previously untreated younger patients with CLL. With the introduction of this ibrutinib-rituximab combination, patients now have a more effective, non-chemoimmunotherapy option," said Koffman.4 "In the 14 years since I was first diagnosed with CLL, the treatment landscape has advanced dramatically for the better, with ibrutinib continuing to play a pioneering role in defining what it means to live with this disease.”
1. FDA approves ibrutinib plus rituximab for chronic lymphocytic leukemia [news release]. FDA. Published April 21, 2020. fda.gov/drugs/drug-approvals-and-databases/fda-approves-ibrutinib-plus-rituximab-chronic-lymphocytic-leukemia. Accessed April 21, 2020.
2. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia. N Engl J Med. doi:10.1056/NEJMoa1817073.
3. Imbruvica (ibrutinib) Receives 11th FDA Approval [news release]. North Chicago, Illinois. Published April 21, 2020. prnewswire.com/news-releases/imbruvica-ibrutinib-receives-11th-fda-approval-301044668.html. Accessed April 21, 2020.
4. U.S. FDA Approves Imbruvica (ibrutinib) Plus Rituximab for the Treatment of Patients with Chronic Lymphocytic Leukemia (CLL). Horsham, Pennsylvania. Published April 21, 2020. prnewswire.com/news-releases/us-fda-approves-imbruvica-ibrutinib-plus-rituximab-for-the-treatment-of-patients-with-chronic-lymphocytic-leukemia-cll-301044670.html. Accessed April 21, 2020.