Results from the Phase 2 RESONATE™-17 (PCYC-1117) study show IMBRUVICA® (ibrutinib) was associated with an 82.6 percent investigator-assessed overall response rate (ORR; the primary endpoint) and a 79 percent progression-free survival (PFS) rate at 12 months in people living with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have a genetic mutation known as deletion 17p (del 17p). These data were presented today by Susan O'Brien, M.D., professor in the Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, at the American Society of Hematology (ASH) Annual Meeting in San Francisco, CA, Janssen Research & Development, LLC (Janssen) announced today. Del 17p occurs when a portion of chromosome 17 has been lost. People with the del 17p mutation are considered to have high-risk disease, which is associated with poor prognosis.
IMBRUVICA is jointly developed and commercialized by Janssen Biotech, Inc. and Pharmacyclics, Inc.
"RESONATE-17 is the largest prospective trial dedicated solely to the study of patients with CLL and SLL who have the del 17p mutation. This subset of patients typically do not respond well to chemotherapies," said O'Brien. "What was compelling about this study was not only the overall response rates seen with IMBRUVICA, but also the duration of these responses. In fact, after thirteen-months of follow-up, investigators determined duration of response had not yet been reached."
"The benefits of IMBRUVICA are evidenced by its robust clinical activity in patients with CLL, even in those with high-risk disease, chromosomal abnormalities or who have already been treated with a number of prior therapies," said Peter F. Lebowitz, M.D., Ph.D., Global Oncology Head, Janssen.
In RESONATE-17, 144 previously treated patients with del 17p (137 with CLL, seven with SLL) received single-agent IMBRUVICA once daily until progression. The primary endpoint of the open-label, single-arm, multicenter RESONATE-17 trial was ORR, as measured by an independent review committee (IRC). Duration of response (DOR), PFS and safety were key secondary endpoints. Investigator-assessed ORR was 82.6 percent and a complete response (CR) or CR with incomplete bone marrow recovery (CRi) occurred in three patients. IRC-assessed ORR was 65 percent. After a median follow-up of 13 months (range 0.5-16.7 months), the median PFS and DOR as assessed by the investigator had not been reached. At 12 months, 79.3 percent of patients were alive and progression-free, with an overall survival (OS) of 88.3 percent.
These data are consistent with the results seen in the pivotal Phase 3 RESONATETM trial, which served as the basis for the July 28, 2014 U.S. Food and Drug Administration (FDA) approval of IMBRUVICA in patients with CLL who have received at least one prior therapy and in CLL patients with del 17p.
The most common Grade 3 or 4 adverse events (AEs) in the RESONATE-17 trial (occurring in five percent or more of IMBRUVICA patients) were neutropenia (low neutrophil count; 14 percent), anemia (8 percent), pneumonia (8 percent) and hypertension (8 percent). The most frequently reported AEs of any grade were diarrhea (36 percent), fatigue (30 percent), cough (24 percent) and arthralgia (joint pain; 22 percent). Atrial fibrillation of any grade was reported in 11 people (7.6 percent). Seven people reported basal or squamous cell skin cancer and one person had plasma cell myeloma. Major hemorrhage was reported in seven people (4.9 percent).
At the time of the data assessment, the median treatment duration was 11.1 months, and 70 percent of people continued treatment with IMBRUVICA.
Abstract #3331: Phase 3 RESONATE Follow-up
A poster presentation by Jennifer Brown, M.D., Ph.D., on Sunday, December 7, provided 16-month follow-up data from the randomized, multicenter, open-label Phase 3 RESONATE trial (N=391), showing an investigator-assessed PFS after 12 months of 84 percent, representing an 89.4 percent reduction in the risk of progression or death versus ofatumumab. After a median follow-up of 16 months, the investigator-assessed PFS was significantly longer in patients taking IMBRUVICA versus ofatumumab (not reached vs. 8.1 months). The median OS in patients receiving IMBRUVICA has not yet been reached, with 18-month survival rates of 85 percent versus 78 percent. The overall investigator-assessed response rate was 90 percent in patients taking IMBRUVICA (versus 25 percent in ofatumumab patients; P<0.0001), including eight percent of patients who achieved a partial response with lymphocytosis.
In an exploratory analysis, Brown showed that patients who had received only one versus two or more prior therapies before IMBRUVICA had a higher PFS (94 percent at 12 months versus 82 percent; P=0.01). An additional analysis also showed the rates of ORR and PFS were similar in patients with or without del 17p, indicating that the high risk del 17p mutation did not confer a worse outcome for patients receiving IMBRUVICA.
Overall, at a median follow-up of 16 months, seventy-six percent of people randomized to IMBRUVICA continued on treatment in the study. In total, 62 percent of patients randomized to receive ofatumumab have crossed over to receive IMBRUVICA, following the recommendation of the Independent Data Monitoring Committee to stop the study early due to a positive interim analysis.
The most common Grade 3 or 4 AEs in the RESONATE trial analysis (occurring in five percent or more of IMBRUVICA patients) were neutropenia (18 percent), pneumonia (9 percent), thrombocytopenia (low platelets in the blood; 6 percent), anemia (6 percent) and hypertension (6 percent). The most frequently reported AEs of any grade were diarrhea (37 percent), nausea (24 percent), fatigue (18 percent) and atrial fibrillation (7 percent). Forty-seven people (24 percent) discontinued IMBRUVICA: 17 due to progressive disease (9 percent), 13 due to AEs (7 percent) and 10 (5 percent) due to death.
Abstract #4696: Phase 3 RESONATE Hematologic and Immunologic Function
A poster presentation by Jacqueline Barrientos, M.D., on Monday, December 8, reported on patient well-being, including hematologic, immunologic and quality of life parameters from the Phase 3 RESONATE trial (N=391). Compared to ofatumumab, IMBRUVICA led to significant improvements in hematologic function and improvements in patient reported outcomes. New episodes of diarrhea were also shown to decline over time along with Grade 3 or higher hematologic AEs and pneumonia.
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