Abstract

Introduction

Ibrutinib is a first-in-class oral inhibitor of Bruton's tyrosine kinase approved for relapsed/refractory mantle cell lymphoma (R/R MCL). We previously reported results of a pooled analysis of 370 patients with R/R MCL treated with ibrutinib in the SPARK (MCL2001; NCT01599949), RAY (MCL3001; NCT01646021), and PCYC-1104 (NCT01236391) studies (median follow-up 24 months; Rule S et al, Br J Haematol [in press]). Here, we present median 3.5 year follow-up in these patients, including additional exposure and follow-up of 87 patients across the 3 studies who enrolled in the long-term access study CAN3001 (NCT01804686).

Methods

Patients enrolled in SPARK, RAY, and PCYC-1104 received ibrutinib 560 mg orally once daily until progressive disease or unacceptable toxicity. Study inclusion and exclusion criteria were similar except patients in SPARK were required to have received both rituximab and bortezomib, and in RAY, prior rituximab. Patients who continued to benefit from ibrutinib therapy at end of study were eligible to enroll in CAN3001, a phase 3b open-label study providing continued access to ibrutinib. Safety reporting in CAN3001 was limited to grade 3/4 adverse events (AEs) and serious adverse events (SAEs). This pooled analysis was limited to patients on ibrutinib therapy, excluding crossover patients. Investigator-assessed tumor response, progression-free survival (PFS), and overall survival (OS) were evaluated. PFS and OS were analyzed by number of prior lines of therapy (LOT) and best tumor response. Patients in CAN3001 were censored from OS analysis upon treatment or study discontinuation. Treatment-emergent adverse events (TEAEs) of ≥ grade 3 were summarized.

Results

Of a total 370 patients, 111 were enrolled in PCYC-1104, 120 in SPARK, and 139 in RAY; 87 of 370 patients subsequently enrolled in CAN3001. The median duration of follow-up in the pooled data set was 41.1 months (95% confidence interval [CI], 37.3-42.5); median treatment exposure was 11.1 months (range: 0.03-72.1). Eighty-three and 40 patients had ibrutinib exposure ≥ 3 and ≥ 4 years, respectively. Fifty-four of 87 (62.1%) patients enrolled in CAN3001 remain on ibrutinib. Patients had a median of 2 (range: 1-9) prior LOT before receiving ibrutinib.

The proportion of patients achieving complete response (CR) increased to 26.5% with 41 months of follow-up. At 2 and 3 years, respectively, 36% (95% CI, 0.31-0.42) and 26% (0.20-0.32) of patients were progression free, and the median PFS was 13.0 months (Table). Median PFS in patients with 1 prior LOT was 33.6 (19.4-42.1) months (Figure) and in patients achieving CR was 46.2 (42.1-not estimable) months (Table). Patients with favorable baseline disease characteristics were more likely to remain on ibrutinib > 3 years.

Overall, 53% (95% CI, 0.47-0.58), 45% (0.39-0.50), and 37% (0.25-0.49) of patients were alive at 2, 3, and 5 years, respectively. Median OS was 26.7 months (Table).

Grade ≥ 3 TEAEs occurred in 295 (79.7%) patients, with the new onset events decreasing after Year 1 (67.8%, 47.8%, 34.8%, 36.1%, and 20.0% for Years 1, 2, 3, 4, and > 4, respectively). Cumulative incidence of any major hemorrhage was 7.3%, and new onset events decreased after Year 1 (4.9%, 2.2%, 2.6%, 2.4%, and 0% for Years 1, 2, 3, 4, and > 4, respectively). The most common (incidence ≥ 5%) grade ≥ 3 TEAEs were neutropenia (17.0%), thrombocytopenia (12.2%), pneumonia (11.9%), anemia (9.5%), atrial fibrillation (5.9%), and hypertension (5.1%). Most of these AEs were more common during the first year of ibrutinib treatment. Treatment-emergent SAEs occurred in 229 (61.9%) patients and new onset SAEs decreased over time (incidence: 47.3%, 33.9%, 29.6%, 25.3%, and 12.5% for Years 1, 2, 3, 4, and > 4, respectively).

Conclusion

In this pooled analysis of ibrutinib-treated R/R MCL patients with median 3.5 years of follow-up, more than a quarter of patients remained progression free and nearly half were alive at 3 years. Clinical outcomes were best for patients who achieved CR and those who were treated with ibrutinib at first relapse/progression. New onset grade ≥ 3 AEs/SAEs decreased over time.

Funding Source

This project was sponsored by Janssen. Writing assistance was provided by Natalie Dennis of PAREXEL and was funded by Janssen Global Services, LLC.

Disclosures

Rule: Sunesis: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Kite: Consultancy; Pharmacyclics: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Celgene: Consultancy, Honoraria; Astra-Zeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Napp: Consultancy. Dreyling: Bayer: Consultancy, Speakers Bureau; Sandoz: Consultancy; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Mundipharma: Consultancy, Research Funding; MorphoSys AG: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau. Goy: Pharmacyclics / J&J: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hess: Celgene: Other: Grants and personal fees; Pfizer: Other: Grants and personal fees; Janssen: Other: Personal Fees; CTI: Other: Grants; Roche: Other: Grants and personal fees. Auer: Janssen: Other: Personal fees; Non-financial support; Bristol Myers Squibb: Other: Personal fees; Celgene: Other: Personal fees. Kahl: Gilead: Other: Personal fees; Infinity: Other: Personal fees; Pharmacyclics: Other: Grants; Personal fees. Londhe: Janssen: Employment, Equity Ownership. Clow: Pharmacyclics: Employment. Deshpande: Janssen: Employment. Parisi: Janssen: Other: Janssen employee. Wang: Karyopharm: Research Funding; Oncoceutics: Research Funding; Juno Therapeutic: Research Funding; Asana: Research Funding; Acerta Pharma: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Karus: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Kite Pharma: Research Funding; Oncternal: Research Funding; BeiGene: Research Funding; Novartis: Research Funding.

Author notes

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Asterisk with author names denotes non-ASH members.