Ibrutinib/Palbociclib Combo Shows Activity in Previously Treated MCL

Peter Martin, MD

Combining ibrutinib (Imbruvica) with the CDK4/6 inhibitor palbociclib (Ibrance) appeared to be well tolerated and active in patients with previously treated mantle cell lymphoma, according to phase I data. ¹

Results of the dose-finding study showed that, at a median follow-up of 25.6 months, the 2-year progression-free survival (PFS) was 59.4% (95% CI, 37.9-80.9), and the 2-year overall survival (OS) was 60.6% (95% CI, 41.1-80.1).

“In this study, we found that the combination of ibrutinib and palbociclib was feasible and active…. We [also] found that responders to ibrutinib-based combinations had a low rate of treatment failure,” the authors, led by Peter Martin, MD, of Meyer Cancer Center, Weill Cornell Medicine, New York, wrote. “Although BTK inhibitor-based combinations appear promising, the degree to which they improve upon single-agent ibrutinib is unclear…. randomized trials will be required to define the true impact on efficacy and safety.”

This study grew out of the authors’ explorations of the fact that nearly half of all MCL patients who receive ibrutinib monotherapy experience treatment failure during the first year. “We previously demonstrated that prolonged early G1 cell cycle arrest induced by the oral, specific CDK4/6 inhibitor palbociclib can overcome ibrutinib resistance in primary human MCL cells and MCL cell lines expressing wild-type BTK,” they wrote.

Martin et al set out to identify the combination’s recommended dose for a phase II trial, which is now ongoing. Their secondary objectives were to explore the regimen’s toxicity and activity profiles.

They enrolled 27 patients who had previously been treated for MCL. Other inclusion factors were good ECOG performance status and adequate function in bone marrow and other organs. Patients who had previously been treated with BTK or CDK4/6 inhibitors were excluded.

Treatment consisted of ibrutinib administered daily and palbociclib administered for 21 days of each 28-day cycle as follows:

Level

Ibrutinib

Palbociclib

Number of patients

Level 1

280 mg

75 mg

3

Level 2

420 mg

75 mg

3

Level 3

420 mg

100 mg

6

Level 4

560 mg

100 mg

10

Level 5

560 mg

125 mg

5

Treatment continued until patients’ disease progressed, toxicities became unacceptable, or they withdrew from the trial.

Martin et al identified the maximum tolerated dose as level 4, ibrutinib 560 mg, and palbociblib 100 mg. At dose level 5, 2 of 5 patients developed grade 3 rash as the dose-limiting toxicity (DLT). One patient experienced DLT at dose level 3, with grade 4 neutropenia that lasted more than 7 days.

Numerous grade 3 to 4 toxicities occurred, including neutropenia (41%), thrombocytopenia (30%), anemia (15%), hypertension (15%), febrile neutropenia (15%), and lung infection (11%). Additionally, 2 patients apiece experienced upper respiratory tract infection (7%), fatigue (7%), increased ALT/AST (7%), rash (7%), hyperglycemia (7%), and myalgia (7%).

Other notable adverse events (AEs) included grade 1 reactivation of viral hepatitis, grade 2 Clostridium difficile infection, grade 3 varicella zoster viral encephalitis, grade 3 influenza A infection, grade 3 atrial fibrillation, grade 3 decreased ejection fraction, grade 3 pneumonitis, and grade 4 gastric hemorrhage. Each of these occurred in 1 patient apiece.

A total of 4 patients required dose interruptions. Eight patients required a dose reduction while on treatment, mostly due to cytopenias.

The authors found no association between PFS and MIPI score, Ki67, or response to last therapy. Eleven patients have died, including 9 deaths related to MCL. Additionally, 1 patient died from complications of allogeneic stem cell transplantation, and 1 died of unknown causes unrelated to MCL or study treatment. The median survival following disease progression was 5 months.

Eighteen patients (67%) responded to treatment; 10 of these patients achieved complete responses (CR; 37%).

Nine patients had not had a documented response to their most recent previous therapy. Of these, 2 patients achieved a CR and 1 achieved a PR. Among 7 patients with a Ki67 >30%, 5 responded, including 3 patients with a CR. Among 7 patients with a high-risk MIPI score, 4 responded. One of these patients had a CR.

Martin et al noted that, despite the apparent durability of responses, “the overall response rate of 67% was similar to the response rate reported in the phase II pivotal trial with single-agent ibrutinib. A comparable experience was noted in the trial of ibrutinib, lenalidomide, and rituximab, which reported a response rate of 76% (CR 56%) and the trial of ibrutinib plus venetoclax, which reported a response rate of 71% (CR 60%),” they wrote.

“Like both of those studies, we found that responders to ibrutinib-based combinations had a low rate of treatment failure, but the roughly one-third of patients with primary BTK inhibitor resistance appear unlikely to be served by BTK inhibitor-based combinations.”^2-4

They recommend that clinicians seek out clinical trials for patients with BTK inhibitor resistance.

References

1. Martin P, Bartlett NL, Blum KA, et al. A phase I trial of ibrutinib plus palbociclib in previously treated mantle cell lymphoma [published online ahead of print January 28, 2019]. Blood. doi: 10.1182/blood-2018-11-886457.
2. Wang ML, Rule S, Martin P, et al. Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma. N Engl J Med. 2013;369(6):507-516.
3. Jerkeman M, Eskelund CW, Hutchings M, et al. Ibrutinib, lenalidomide, and rituximab in relapsed or refractory mantle cell lymphoma (PHILEMON): a multicentre, open-label, singlearm, phase 2 trial.
4. Tam CS, Anderson MA, Pott C, et al. Ibrutinib plus venetoclax for the treatment of mantle-cell lymphoma. N Engl J Med. 2018;378(13):1211-1223.