Imbruvica Plus Obinutuzumab Shown to Increase Survival for Leukemia/Lymphoma

Janssen Pharmaceutical announced results from the Phase 3 iLLUMINATE (PCYC-1130) study, which showed the combination of Imbruvica (ibrutinib) plus obinutuzumab significantly improved progression-free survival (PFS) versus chlorambucil plus obinutuzumab in patients with newly diagnosed chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), the most common form of leukemia in adults. In addition, Imbruvica data from the Phase 1b/2 study and its extension study (PCYC-1102, PCYC-1103) with up to seven years of follow-up in patients with newly diagnosed and relapsed/refractory (R/R) CLL/SLL, demonstrated durable, long-term survival benefits as a monotherapy, representing the longest follow-up for a Bruton's tyrosine kinase (BTK) inhibitor in CLL/SLL. Imbruvica, a BTK inhibitor studied in patients with CLL for up to seven years, is jointly developed and commercialized by Janssen Biotech, and Pharmacyclics.

"These long-term results suggest that 80 percent of newly diagnosed patients with chronic lymphocytic leukemia receiving Imbruvica monotherapy sustained remission through seven years without chemotherapy. Together with the iLLUMINATE study findings, these data provide compelling evidence to consider Imbruvica as a single agent or combination option for appropriate newly diagnosed patients with CLL," said Craig Tendler, M.D., Vice President, Clinical Development and Global Medical Affairs, Janssen Research & Development. "Since its first approval more than five years ago, Imbruvica has been regarded as an important treatment in CLL, and we continue to study and pursue its full potential across the spectrum of blood cancers through our comprehensive clinical development programs."

At a median follow-up of 31.3 months, Imbruvica plus obinutuzumab significantly prolonged the Independent Review Committee (IRC)-assessed PFS compared with chlorambucil plus obinutuzumab (median not reached [NR] vs. 19.0 months; HR 0.23; 95 percent confidence interval [CI]: 0.15-0.37; P<0.0001), with a 77 percent reduction in risk of progression or death.

Superior PFS in the Imbruvica plus obinutuzumab arm compared to the chlorambucil plus obinutuzumab arm was also seen in the high-risk population, including those with unmutated IGHV, del11q, del17p and/or TP53 mutation, with an 85 percent reduction in risk of progression or death (median NR vs. 14.7 months; HR 0.15; 95 percent CI: 0.09-0.27; P<0.0001). In addition, IRC-assessed overall response rate (ORR) was higher in the IMBRUVICA plus obinutuzumab arm versus the chlorambucil plus obinutuzumab arm (88 percent vs. 73 percent); complete response (CR)/complete response with incomplete blood recovery (CRi) rates were also higher with 19 percent versus 8 percent, respectively. Minimal residual disease (MRD) was undetectable in blood and/or bone marrow (<10-4 by flow cytometry) for 35 percent of patients treated with IMBRUVICA plus obinutuzumab, compared to 25 percent of patients treated with chlorambucil plus obinutuzumab. Overall survival (OS) rates at 31 months were 86 percent for the Imbruvica plus obinutuzumab arm compared to 85 percent for the chlorambucil plus obinutuzumab arm.

The most common Grade 3 or higher adverse events (AEs) in the Imbruvica plus obinutuzumab arm versus chlorambucil plus obinutuzumab arm were neutropenia (43 percent vs. 63 percent), thrombocytopenia (35 percent vs. 25 percent), diarrhea (34 percent vs. 10 percent), cough (27 percent vs. 12 percent), infusion-related reactions (IRRs; 25 percent vs. 58 percent), arthralgia (22 percent vs. 10 percent), pyrexia (19 percent vs. 26 percent), anemia (17 percent vs. 25 percent), and nausea (12 percent vs. 30 percent). No patients discontinued obinutuzumab due to IRRs in the IMBRUVICA plus obinutuzumab arm compared to the chlorambucil plus obinutuzumab arm (6 percent). AEs led to the discontinuation of Imbruvica in 16 percent of patients and led to the discontinuation of chlorambucil in 9 percent of patients. AEs led to the discontinuation of obinutuzumab in the Imbruvica plus obinutuzumab arm (9 percent) and chlorambucil plus obinutuzumab arm (13 percent). With about three years of follow-up, 70 percent of patients in the Imbruvica plus obinutuzumab arm remain on Imbruvica monotherapy.

iLLUMINATE (PCYC-1130) evaluated newly diagnosed patients with CLL/SLL who were randomized to receive IMBRUVICA 420 mg once-daily continuously until disease progression or unacceptable toxicity in combination with obinutuzumab 1000 mg intravenously over 6 cycles (n=113), or chlorambucil on Days 1 and 15 of each cycle plus obinutuzumab 1000 mg intravenously over 6 cycles (n=116). Median age of the patients was 71 years and 65 percent of the patients had high-risk genomic features.

With up to seven years of follow-up, the studies (Phase 1b/2, PCYC-1102 and its extension, PCYC-1103) evaluated newly diagnosed and R/R patients with CLL/SLL (n=132; newly diagnosed=31, R/R=101), including those with high-risk features who received 420 mg or 840 mg once-daily Imbruvica until disease progression or unacceptable toxicity. As of the cutoff, 55 percent of newly diagnosed and 21 percent of R/R patients continued Imbruvica with median follow-up of 67 months.

Results from these studies showed durable efficacy of Imbruvica in newly diagnosed and R/R patients with CLL/SLL. These long-term data showed sustained PFS and OS rates. The estimated seven-year PFS rates were 80 percent for patients with newly diagnosed disease and 32 percent for patients with R/R disease. Notably, administering Imbruvica in earlier lines of therapy resulted in improved PFS outcomes for R/R patients.

ORR was 89 percent for all patients (CR, 15 percent) with similar rates in newly diagnosed (87 percent [CR, 32 percent]) and R/R CLL/SLL patients (89 percent [CR, 10 percent]). Median duration of response (DOR) was NR (95 percent CI: 0+-85+) for newly diagnosed CLL/SLL patients and was 57 months (95 percent CI: 0+-85+) for R/R CLL/SLL patients. Median PFS was NR (95 percent CI: NE, NE) for newly diagnosed CLL/SLL patients and was 51 months (95 percent CI: 37-70) for R/R CLL/SLL patients. The median OS was NR in newly diagnosed (95 percent CI: 80-NE) or R/R CLL/SLL patients (95 percent CI: 63-NE) with estimated 7-year OS rates of 75 percent and 52 percent, respectively.

Grade 3 or higher AEs were reported in 74 percent of newly diagnosed and 89 percent of R/R patients with CLL/SLL. Hypertension (newly diagnosed, 32 percent; R/R, 26 percent), diarrhea (newly diagnosed, 16 percent; R/R, 4 percent), and hyponatremia (newly diagnosed, 10 percent; R/R, 0 percent) were among the most common Grade 3 or higher treatment-emergent AEs. Major hemorrhage and Grade 3 or higher atrial fibrillation, thrombocytopenia, anemia, and arthralgia were observed in 11 percent or less of newly diagnosed and R/R patients. In addition, infections (newly diagnosed, 23 percent; R/R, 55 percent) was more common in R/R CLL/SLL patients. No new or unexpected AEs were observed, and the occurrence of most Grade 3 or higher AEs and serious AEs decreased over time, with the exception of hypertension.

Imbruvica (ibrutinib) is a first-in-class, once-daily oral medicine that works differently than chemotherapy as it blocks the Bruton's tyrosine kinase (BTK) protein. The BTK protein sends important signals that tell B cells to mature and produce antibodies; BTK signaling is needed by specific cancer cells to multiply and spread. By blocking BTK, Imbruvica may help move abnormal B cells out of their nourishing environments in the lymph nodes, bone marrow, and other organs.

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