Palbociclib Enhances Ibrutinib's Impact in MCL

Peter Martin, MD

Palbociclib (Ibrance) can help patients with mantle cell lymphoma (MCL) overcome resistance to ibrutinib (Imbruvica), according to phase I results presented at the 2016 ASH Annual Meeting.¹

The overall response rate (ORR) with the combination of the CDK4/6 and BTK inhibitors was 64%, with a complete response (CR) rate of 43% and a median time to CR of 3 months. The estimated 1-year progression-free survival (PFS) rate was 61%.

“About one-third patients on ibrutinib do not respond to the drug, and so combination treatments are warranted,” Martin said. Previous studies by our group—in cell lines expressing wild-type BTK and in primary human samples—showed that treatment with the G1-specific CDK4/6 inhibitor palbociclib can overcome ibrutinib resistance,²” lead study author Peter Martin, MD, associate professor of Medicine at Weill Cornell Medical College, Cornell University, said when discussing the data at ASH. “We found that prolonged cell cycle arrest could sensitize cells to death by a PI3K or BTK inhibitor.”

Based on the in vitro observations, the current phase I trial was designed to evaluate the safety and preliminary activity of palbociclib plus ibrutinib in patients with previously treated MCL. The primary objective of the trial was to select the recommended phase II dose for the combination of ibrutinib and palbociclib, with secondary objectives of characterizing the toxicity profile and estimating the ORR, CR rate, and PFS.

The primary eligibility criteria for trial enrollment, Martin said, were adults who were previously treated for MCL without receiving CDK4/6 or BTK inhibitors. Further, patients should have had acceptable marrow and organ function. The median age of the 23 enrolled patients was 65 years (range, 42-81), and a majority were male. Fourteen of the 23 had received prior autologous stem cell transplant.

Five dose level combinations were evaluated in the trial: (1) 280 mg of ibrutinib plus 75 mg of palbociclib; (2) 420 mg of ibrutinib plus 75 mg of palbociclib; (3) 420 mg of ibrutinib plus 100 mg of palbociclib; (4) 560 mg of ibrutinib plus 100 mg of palbociclib; and (5) 560 mg of ibrutinib plus 125 mg of palbociclib.

Patients were treated in 28-day cycles—ibrutinib was administered daily and palbociclib was administered on days 1 to 21. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent. Patients were evaluated for efficacy at the end of cycles 3 and 6, and every 6 cycles thereafter. Patient response to treatment was monitored with CT and confirmed by PET/CT.

Overall, 19 of 21 patients had a response to treatment, with 9 achieving a CR: 3 at dose level 1, 1 at dose level 2, and 2 at dose level 3. A partial response was observed in 4 patients, 1 each at dose levels 2 and 4 and 2 at dose level 3. Disease progression was observed in 1 patient.

The most common grade 1/2 adverse events (AEs) included diarrhea (50%), fatigue (44%), rash (39%), bruising (17%), nausea (17%), fever (11%), dyspepsia (11%), and myalgia (11%).

The most frequent grade 3/4 hematologic AEs included thrombocytopenia (28%), neutropenia (22%), and lymphopenia (17%). Nonhematologic grade 3/4 AEs, occurring in 1 patient each, included lung infection, encephalitis, hyponatremia, sinus tachycardia, pneumonitis, and increased ALT/AST levels.

Thirteen patients continued participating in the trial, while 4 dropped out due to disease progression, 2 due to AE, and 1 to undergo allogeneic stem cell transplantation.

Two patients experienced grade 3 rash at dose level 5, and were the only patients who required dose reductions; 6 patients required dose interruptions. Dose level 4 (ibrutinib at 560 mg daily and palbociclib at 100 mg x 21/28 days) was established as the maximum-tolerated dose for further studies, Martin said.

Martin et al concluded that the mechanism-based combination of ibrutinib plus palbociclib was well tolerated in their study and showed activity. Biomarker studies to evaluate mechanisms of primary resistance are ongoing and a phase II multicenter study is planned, said Martin.

This article was repurposed from AJMC.com.

References

1. Martin P, Blum K, Bartlett NL, et al. A phase I trial of ibrutinib plus palbociclib in patients with previously treated mantle cell lymphoma. Presented at: 58th American Society of Hematology Annual Meeting; December 2-6, 2016; San Diego, CA. Abstract 150.
2. Chiron D, Di Liberto M, Martin P, et al. Cell-cycle reprogramming for PI3K inhibition overrides a relapse-specific C481S BTK mutation revealed by longitudinal functional genomics in mantle cell lymphoma. Cancer Discov. 2014;4(9):1022-1035.