Photo courtesy of
Janssen Biotech, Inc.
NEW YORK—Long-term follow-up of single-agent ibrutinib at the approved dose of 420 mg daily confirms that the Bruton’s tyrosine kinase inhibitor produces rapid and durable responses in patients with chronic lymphocytic leukemia (CLL), according to an update presented at Lymphoma & Myeloma 2015.
At up to 44 months of follow-up, the median duration of response (DOR) and progression-free survival (PFS) have not yet been reached.
At 30 months, the PFS rate was 96% for treatment-naïve patients and 76% for relapsed or refractory patients. Patients with del 17p had a median PFS of 32.4 months.
“Virtually all the patients do respond to treatment,” said Steven Coutre, MD, of Stanford University School of Medicine in California.
“Only a handful of patients achieve less than CR [complete response] or PR [partial response],” he said during his presentation at the meeting.
Phase 1/2b and extension studies
Ninety-four patients enrolled in the phase 1/2b (PCYC-1102) and extension (PCYC-1103) studies received 420 mg of ibrutinib once daily.
“We initially enrolled patients with relapsed/refractory CLL,” Dr Coutre clarified. “Then, because of the significant efficacy and safety that was observed, we added a second cohort of treatment-naïve patients age 65 and older.”
The treatment-naïve (TN) cohort consisted of 27 CLL patients. The relapsed or refractory (R/R) cohort consisted of 67 patients with CLL or small lymphocytic lymphoma, including patients with high-risk disease, which was defined as disease progression less than 24 months after the start of a chemoimmunotherapy regimen or refractory to the most recent regimen.
The median time on study was 32 months (range, 0–44).
In the TN cohort, the median age was 71, 78% were ECOG performance status 0, and most had advanced disease as indicated by Rai stage.
In the R/R cohort, the median age was 66, 40% were ECOG performance status 0, 57% were ECOG performance status 1, and 52% had bulky nodes greater than 5 cm.
“We had a significant representation of high-risk cytogenetic abnormalities,” Dr Coutre noted.
In the R/R group, 34% of patients had del 17p, and 33% had del 11q. In the TN cohort, 7% of patients had del 17p, and none had del 11q.
“There were also a significant number of cytopenias,” Dr Coutre said, “as one might expect in a heavily pretreated patient population.”
The number of prior therapies was also “quite significant,” he said, with 55% having a median of 4 or more therapies (range, 1–12).
“It really stretches the imagination to figure out what those 12 different regimens were,” he commented.
All R/R patients had prior chemotherapy, 94% a nucleoside analog, 90% an alkylator (including bendamustine), 99% anti-CD20-based therapy, 97% anti-CD20-based chemoimmunotherapy, 24% alemtuzumab, and 6% idelalisib.
The median time on treatment was 30.4 months (range, 1.3–44.2) for TN patients and 21.9 months (range, 0.3–44.6) for R/R patients. The majority of patients in both groups remain on ibrutinib—81% of the TN patients and 60% of R/R patients.
Safety
“Only 1 patient in the treatment-naïve cohort has progressed,” Dr Coutre noted. “That was a patient with deletion 17p [who progressed in about 8 months].”
The primary reasons for discontinuing therapy were progressive disease (1 TN, 11 R/R), adverse events (AEs; 3 TN, 9 R/R), consent withdrawal (1 TN, 2 R/R), investigators’ decision (0 TN, 4 R/R), and other reasons (0 TN, 1 R/R).
“Discontinuations due to AEs occurred predominantly early,” Dr Coutre observed. “So of the 12 patients [who discontinued due to AEs], 7 discontinued in the first year, 3 in the second year, and only 2 beyond year 3.”
Grade 3 or higher AEs occurred in 55 R/R patients (82%) and 17 TN patients (63%). Infection occurred in 48% of R/R patients and 11% of TN patients. Dr Coutre pointed out that most of these AEs were not related to ibrutinib.
Grade 3 or higher ibrutinib-related AEs occurred in 6 TN patients (22%) and 25 R/R patients (37%). One TN patient and 8 R/R patients experienced grade 3 or higher serious ibrutinib-related AEs.
One TN patient and 7 R/R patients required a dose reduction due to an AE. However, the dose reductions occurred predominantly during the first year, Dr Coutre noted.
Regarding time to onset of grade 3 or higher AEs, Dr Coutre said most of the events occurred early and decreased with time. Pneumonia and atrial fibrillation followed this pattern, as did neutropenia and thrombocytopenia. Hypertension was the exception, occurring during all years.
Nonhematologic AEs of grade 3 or higher that occurred in at least 5% of patients were pneumonia, hypertension, diarrhea, hyponatremia, and atrial fibrillation in TN patients, and sepsis, cellulitis, dehydration, and fatigue in R/R patients.
Hematologic AEs of grade 3 or higher in each cohort included neutropenia, thrombocytopenia, and anemia.
“The drug doesn’t seem to be myelosuppressive,” Dr Coutre noted. “We don’t have prolonged cytopenias as patients stay on treatment.”
One TN patient and 7 R/R patients died during the study.
Response and survival
The response rate (as assessed by the investigators) was 85% for TN patients. Twenty-six percent of patients achieved a complete response, 52% a partial response (PR), and 7% a PR with lymphocytosis.
The response rate for R/R patients was 94%. Nine percent achieved a complete response, 82% a PR, and 3% a PR with lymphocytosis.
The median time to the best response was 7.4 months for both cohorts.
The median DOR has not been reached in either cohort, but the 30-month DOR was 95.2% for TN patients and 79.1% for R/R patients.
The 30-month PFS was 95.8% for TN patients and 75.9% for R/R patients.
At 30 months, the PFS rate was 59.6% for patients with del 17p and 82.4% for patients with del 11q. The median PFS for patients with del 17p was 32.4 months, and it was not reached for patients with del 11q. For patients with neither of these abnormalities, the median PFS has not been reached.
“Overall survival was equally impressive,” Dr Coutre said.
The median overall survival has not been reached for any group, and 30-month overall survival is 81.3% for del 17p patients, 88.2% for patients with del 11q, and 90.3% for patients with neither abnormality.
“[I]brutinib induces rapid and durable responses that continue to improve over time . . . ,” Dr Coutre said.
He added that the drug is well-tolerated, “allowing us to continue patients on treatment, which, I think, is particularly important for these types of drugs because we clearly see that patients have significant clinical benefit, despite the fact that they still often have easily detectable disease, particularly in the bone marrow.”
“So one of the challenges is going to be [to determine] how to use these drugs on a long-term basis and [see if we can] use them in a more time-limited fashion.”
Ibrutinib is approved by the US Food and Drug Administration for 4 indications: patients with CLL who have received at least 1 prior therapy, CLL patients with del 17p, patients with mantle cell lymphoma, and patients with Waldenström’s macroglobulinemia.
Ibrutinib is distributed and marketed as Imbruvica by Pharmacyclics and also marketed by Janssen Biotech, Inc.
