Tag: ibrutinib

The Story of Ibrutinib in Mantle Cell Lymphoma

Picture1By Peter Martin, MD

Just over one year ago, in November 2013, the United States Food and Drug Administration (FDA) approved the oral drug ibrutinib for patients with previously treated mantle cell lymphoma (MCL). The FDA based its decision upon promising results from the PCYC-1104 trial that took place at several centers around the world, including Weill Cornell Medical College (WCMC). During the 56th Annual Meeting of the American Society of Hematology, long-term follow up from the PCYC-1104 trial was presented. At the two year time point, roughly one third of patients remain free from progression. Moreover, serious side effects appear to become less frequent with time.

Because bias and chance can sometimes lead to promising results, investigators from around the world, including WCMC performed a second trial (MCL2001) to evaluate the effects, good and bad, of ibrutinib in 120 patients with previously treated MCL. Preliminary data from MCL2001 was also presented during ASH, and they appear to be consistent with the PCYC-1104. With roughly 15 months of follow up, two-thirds of patients responded and responses lasted for a little more than one year on average. No new side effects were identified.

Finally, preliminary results from the MCL4001 Early Access Program (EAP), were presented. The EAP was designed to provide ibrutinib to patients with relapsed or refractory MCL prior to its approval by the FDA and was open at several sites around the world, including WCMC. One hundred forty-nine patients with MCL received daily oral ibrutinib and were followed for safety. Like the PCYC-1104 and MCL2001 trials, MCL4001 confirmed the safety of ibrutinib. Less than 10% of patients stopped ibrutinib due to an adverse event and most patients continued to receive ibrutinib through the EAP until the FDA approved it. Taken together, these three trials confirm the important role of ibrutinib in the management of mantle cell lymphoma.

Unfortunately, despite the recognized efficacy of ibrutinib in patients with MCL, roughly one-third of patients are resistant and among those that respond, secondary resistance to ibrutinib is common. In a retrospective cohort study we identified 32 patients at WCMC and Ohio State University, who experienced progression of lymphoma while receiving ibrutinib. There was no clear association between prior number of therapies, ibrutinib response, morphology, Ki67 prior to ibrutinib, response to ibrutinib, duration of ibrutinib, or choice of subsequent therapy and overall survival. Ultimately primary and secondary ibrutinib resistance was associated with poor clinical outcomes, and there were no identifiable predictors of response to subsequent therapy following development of ibrutinib resistance.

These data underscore the importance of ongoing research in MCL. As we learn more about potential mechanisms of resistance to ibrutinib we are able to design rational combinations that build on the remarkable safety and activity of the drug. Moreover, there is clearly a need for new treatments that have the potential to help patients that experience progression of lymphoma while on ibrutinib. Fortunately, investigators at WCMC and around the world have identified the emergence of this new unmet need and are working on new treatment options. Stay tuned to the WCMC Lymphoma Program Blog for new developments.

Ibrutinib is a Highly Effective Therapy for Patients with Relapsed or Refractory CLL or SLL with 17p deletion: Results from the Phase II RESONATE -17 Trial

Picture3By Dr. Richard Furman, MD

Patients with chronic lymphocytic leukemia (CLL) with deletion of the short arm of chromosome 17 (del 17p) follow an aggressive clinical course and demonstrate a median survival of less than 2 years. Ibrutinib is a first-in-class inhibitor of Bruton’s tyrosine kinase (BTK), currently approved as treatment for CLL patients relapsed after one prior therapy or patients with del 17p at any line of therapy. Ibrutinib’s initial approval was based upon phase II data published in June 2013. The expanded approval is based upon results from the RESONATE trial comparing ibrutinib to ofatumumab.

At the 56th annual meeting of the American Society of Hematology (ASH), investigators presented the results of the phase II RESONATE -17 (PCYC-1117-CA) study investigating ibrutinib in relapsed CLL patients with deletion of 17p.

The study was designed to evaluate the efficacy and safety of single-agent ibrutinib as treatment of patients with relapsed or refractory CLL with del 17p or small lymphocytic leukemia (SLL). 144 patients (137 CLL patients, 7 SLL patients)  were enrolled and received ibrutinib 420 mg once daily until progression. The primary endpoint was overall response rate (ORR), with secondary endpoints including duration of response (DOR), progression-free survival (PFS), and safety of ibrutinib.

At a median follow up of 13 months, the median PFS and DOR had not been reached. At 12 months, 79.3% of patients were alive and progression-free, and 88.3% of responders were progression-free, with only 20 patients (13.9%) reporting progressive disease. At the time of data cut, the median treatment duration was 11.1 months, and 101 of 144 patients (70%) continued treatment with ibrutinib.

Efficacy results were consistent with earlier results, and the PFS compares favorably to that of treatment-naïve del 17p CLL patients receiving FCR or alemtuzumab. These results support ibrutinib as an effective therapy for patients with del 17p CLL/SLL.

Updated Efficacy Results of Ibrutinib Compared with Ofatumumab in Relapsed CLL (RESONATE Trial), with Analysis of Genetic and Prognostic Subgroups

Picture3By Dr. Richard Furman, MD

The role of various prognostic factors in CLL/SLL is not yet fully understood, including the implications of new genetic markers associated with high risk. Ibrutinib is a first-in-class Bruton’s tyrosine kinase inhibitor that is approved for the treatment of CLL patients who have received at least 1 prior therapy, and for patients with 17p deletion CLL. In results presented before the 56th annual meeting of the American Society of Hematology, updated efficacy results from the phase 3 RESONATE (PCYC-1112) study comparing ibrutinib to ofatumumab were reported.

In the phase III study 391 randomized patients received 420 mg daily of ibrutinib or ofatumumab daily, until disease progression or unacceptable toxicity for up to 24 weeks. During an interim analysis at the median follow up of 9.4 months, patients in the ofatumumab arm were provided access to the ibrutinib arm.

Comparatively, progression free survival (PFS) was significantly longer for ibrutinib compared to ofatumumab. Overall survival (OS) was significantly better for ibrutinib compared to ofatumumab, with 18-month OS rates of 85% and 78% respectively. Higher number of prior therapies (≥3) and 11q deletion were associated with significantly lower 12-month PFS rate for ofatumumab, but not for ibrutinib. The overall response rate (ORR) for ibrutinib versus ofatumumab was 90% to 25%. Compared to ofatumumab, ibrutinib improved 12-month PFS and ORR regardless of baseline genetics, complex cytogenetics, or number of prior therapies. No significant difference in 12-month PFS was observed in ibrutinib treated patients with or without del(17p) or for those who developed lymphocytosis compared to those without lymphocytosis. Median treatment duration was longer for ibrutinib versus ofatumumab and was 16 to 5 months respectively.

In this one on one comparison ibrutinib significantly outperformed ofatumumab in PFS, OS, and ORR in patients with CLL/SLL with at least one prior therapy. These results are consistent with previously published findings, and provide further evidence for the clinical utility  of ibrutinib in patients with CLL.