Steven Coutre, MD
Single-agent ibrutinib (Imbruvica) demonstrated an overall response rate (ORR) of 91%, including a complete response rate of 14%, in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to follow-up data from 94 patients treated in the phase I/IIb study PCYC-1102 and the PCYC-1103 extension study.
After up to 45 months of follow-up for the 94 patients treated with ibrutinib, the ORR was 85% in 27 treatment-naive (TN) patients and 94% in 67 relapsed/refractory (R/R) patients. Complete response rates were 26% (n = 7) and 9% (n = 6) for the TN and R/R patients, respectively.
The median treatment duration was 25 months (range, 0-45 months) for all patients (30 months TN; 22 months R/R). The median duration of response (DOR) and progression-free survival (PFS) have not yet been reached. The 30-month PFS rate was 96% in TN and 76% in R/R patients with CLL. The median number of prior therapies for R/R patients was four (range, 1-12 therapies). One patient with previously untreated CLL experienced disease progression during the follow-up.
Steven Coutre, MD, presented the follow-up data at the 2015 AACR Annual Meeting. In an interview with OncLive
, Coutre, professor of Medicine (Hematology) at Stanford University Medical Center, called the results promising, while noting that ibrutinib has significantly impacted the treatment of patients with CLL, since its approval in 2014.
“What this study really demonstrates is the continued benefit that patients receive from the drug,” said Coutre. “The efficacy and response rates have continued to improve.”
The most frequently reported grade 3 or greater adverse events in the trial were hypertension (23%), pneumonia (15%), neutropenia (13%), atrial fibrillation (7%) and diarrhea (7%). During follow-up, 12 patients discontinued treatment due to disease progression. Discontinuation due to AEs declined over time; in total, 12 patients discontinued due to an AE (seven patients in year 1, three patients in year 2, and two patients beyond year 3).
These minimal side effects are what make the ibrutinib groundbreaking for the treatment of CLL and SLL patients, said Coutre.
“The drug has had significant impact,” he explained. “It is a very well tolerated therapy for patients who may not be able to tolerate standard chemoimmunotherapy or patients that no longer respond to standard therapy. There is a lack of late side effects. The side effects related to the treatment have actually decreased over time.”
All patients received ibrutinib 420 mg daily, dosed until disease progression in the PCYC-1102 and the PCYC-1103 extension study. The best ORR, including partial response with lymphocytosis (PR-L), was assessed by investigators using IWCLL criteria. The majority of patients entered the study with baseline cytopenias. Early and sustained improvements in hemoglobin and platelet counts were observed.
Ibrutinib is a first-in-class, once-daily, oral, covalent inhibitor of Bruton’s tyrosine kinase. It was granted an accelerated approval for the treatment of patients with CLL who have received at least one previous therapy in February 2014. This approval was based on early data from the phase Ib/II PCYC-1102-CA study in which ibrutinib demonstrated an ORR of 58.3% in previously treated CLL across all subtypes, with duration of response up to 24.2 months.
The drug was granted a full approval in July 2014, based on the phase III RESONATE study, which demonstrated a durable improvement in ORR, PFS, and overall survival (OS) compared with ofatumumab. This study was unblinded 4 months after the enrollment of the last patient. At the first analysis, 57 patients in the ofatumumab group had crossed over to receive ibrutinib following progression.
For the primary endpoint of PFS, the median in the ibrutinib arm was not reached compared with an 8.1-month median with ofatumumab (HR = 0.22, 95% CI, 0.15–0.32, P < .0001). At 6 months, 88% of patients treated with ibrutinib were disease-free compared with 65% in the ofatumumab group. In patients with a 17p13.1 deletion, the HR was 0.25 (95% CI, 0.14-0.45), warranting a separate FDA approval for high-risk patients with these alterations.
For the secondary endpoint of OS, ibrutinib also demonstrated superior efficacy. At 12 months, the OS rate was 90% for patients treated with ibrutinib compared with 81% in the ofatumumab group. The median OS was not reached for patients treated with ibrutinib (HR = 0.43; 95% CI, 0.24-0.79; P = .005).
Recently the phase III HELIOS study, which examined ibrutinib in combination with bendamustine and rituximab (BR), was unblinded following the demonstration of a significant extension in PFS with the triplet compared with BR alone in patients with CLL or SLL. Full data from the trial were submitted for presentation at the 2015 ASCO Annual Meeting and are being prepared for regulatory submission.
In a preceding phase Ib study exploring ibrutinib plus BR, the estimated 12-month PFS was 90% in 30 patients with relapsed/refractory CLL/SLL. The ORR with the combination was 93%.
The FDA initially approved ibrutinib for patients with MCL who received at least one prior therapy in November 2013. In late January 2015, the FDA expanded this indication to include the treatment of patients with Waldenström’s macroglobulinemia.