FDA Grants Priority Review to Ibrutinib Plus Obinutuzumab in Frontline CLL

Danelle James, MD

The FDA has granted a priority designation to a supplemental new drug application (sNDA) for ibrutinib (Imbruvica) for use in combination with obinutuzumab (Gazyva) for the frontline treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

The sNDA is based on data from the phase III iLLUMINATE (PCYC-1130) trial, which showed that frontline treatment with ibrutinib combined with obinutuzumab significantly improved progression-free survival (PFS) compared with chlorambucil plus obinutuzumab in patients with CLL/SLL. AbbVie (Pharmacyclics) and Janssen Biotech, the codevelopers of ibrutinib, reported in a press release that the data from the study will be shared at a future medical meeting.

Under the priority designation, the FDA will review the sNDA within 6 months from the acceptance of the filing, compared with the standard 10 months.

"Our robust clinical research program with Imbruvica continues to reinforce the evidence for its use as an efficacious treatment option in CLL and SLL, this time versus a National Comprehensive Cancer Network guidelines Category 1 treatment, which is the chemoimmunotherapy combination of chlorambucil plus obinutuzumab," Danelle James, MD, head of Clinical Science, Pharmacyclics, said in a press release.

"Further, for the first time in CLL, results from iLLUMINATE have shown the potential benefits of using an Imbruvica-based, chemotherapy-free, anti-CD20 combination. Since its initial approval 5 years ago, Imbruvica has received 9 FDA approvals across 6 different diseases, and we remain committed to advancing new research to understand its full potential in blood cancers like CLL and SLL, as well as other difficult-to-treat diseases with unmet medical needs," added James.

The open-label, multicenter, phase III iLLUMINATE trial (NCT02264574) randomized treatment-naïve patients with CLL/SLL to 420 mg of ibrutinib continuously combined with 1000 mg of IV obinutuzumab over 6 cycles, or the same regimen of obinutuzumab combined with chlorambucil on day 1 and day 15 of each cycle. Accrued patients were aged ≥65 years or if younger, had a cumulative Illness rating score (CIRS) >6 or creatinine clearance estimated at <70 mL/min. Beyond the primary endpoint of PFS, secondary endpoints included overall response rate (ORR) and the rate of minimal residual disease (MRD)-negative responses.

Phase II data from the Icll-07 Filo study (NCT02666898) presented at the 2017 ASH Annual Meeting previously demonstrated positive clinical activity for frontline ibrutinib/obinutuzumab in patients with CLL. Between November 2015 and May 2017, the study accrued 135 previously untreated patients with a median age of 62.5 (range, 35-80). There were 89 males and 46 females.

Per the Binet staging system, 8.2% of patients were stage A, 67.2% were stage B, and 24.6% were stage C. Ninety-nine percent of patients had an ECOG performance status of 0 or 1, with one patient having an ECOG performance status of 2. Twenty-five patients had del11q, 51 had del13q, and 21 had trisomy 12. Ten patients had a complex karyotype (>3 abnormalities).

At 9 months’ follow-up, the ORR was 100% among 73 evaluable patients. The response rate comprised a complete remission rate of 37% and a partial remission rate of 63%. However, the researchers did note in the conclusion of their ASH abstract that, “The majority of the patients required subsequent immunochemotherapy because of detectable bone marrow minimal residual disease.”

There were 24 serious adverse events related to treatment, with the most common being cardiac events (n = 5), grade 3 tumor lysis syndrome (n = 3), grade 4 febrile neutropenia (n = 3), and grade 3 neutropenia (n = 2). There were 2 on-study patient deaths at the data cutoff, 1 of unknown cause and 1 of a brain hemorrhage after a fall on the stairs not caused by the therapy.

Michael Choi, MD, UC San Diego Medical Center, commented on these initial Icll-07 Filo study data in an Insights segment on OncLive.

“This trial had all patients receive obinutuzumab and ibrutinib in combination at first with the thought that patients who have detectable disease would then receive standard chemoimmunotherapy afterwards with the goal of ultimately achieving MRD-negative remissions,” said Choi.

“They’ve reported on the patients up until that first endpoint with the combination of ibrutinib and obinutuzumab. They also reported the universally successful outcomes with a 100% response rate. But they did note that not all patients, or not many patients, achieved that MRD negativity—I think it was about 10% or so. So, they did note that most of the patients still needed to receive chemoimmunotherapy afterwards with the goal of achieving MRD negativity. I do think that this study is still successful in showing the feasibility of that combination and the safety of that combination, as well as that the combination did achieve high response rates.”

Michallet AS, Dilhuydy MS, Subtil F, et al. Phase II, multicenter trial, exploring “chemo-sparing” strategy associating obinutuzumab + ibrutinib followed by a MRD driven strategy, in previously untreated symptomatic medically fit chronic lymphocytic leukemia patients (CLL): preliminary results of the induction phase of the Icll-07 filo study. Presented at: the 59th ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, GA. Abstract 497.