Ibrutinib and Palbociclib: A New Combination for Mantle Cell Lymphoma?

The combination of ibrutinib and the CDK-4/6 inhibitor palbociclib could be safely administered to patients with previously treated mantle cell lymphoma (MCL), according to results from a phase I trial published in Blood.

This regimen also was associated with a response rate that was similar to that reported in historical studies of single-agent ibrutinib, the authors, led by Peter Martin, MD, of Weill Cornell Medicine in New York, wrote.

“Bruton tyrosine kinase (BTK) inhibition will likely be the mainstay of therapy for several years to come in patients with previously treated disease,” Dr. Martin told ASH Clinical News, explaining the rationale for the trial. “The challenge is that BTK inhibitors don’t work for everybody, or forever, with most patients developing resistance within 10 to 14 months.”

Earlier research demonstrated that palbociclib induced prolonged cell cycle arrest in MCL tumor cells; based on these observations, the investigators evaluated whether treatment with palbociclib could overcome ibrutinib resistance in a cohort of 27 patients with previously treated MCL.

Patients were eligible if they had adequate bone marrow/organ function, good performance status, and no previous treatment with BTK or CDK4/6 inhibitors. Their median age was 65 years (range = 42-81 years), and the median number of prior therapies was one (range = 1-5).

Participants received once-daily ibrutinib plus palbociclib in one of the five following schedules:

  • level 1: ibrutinib 280 mg and palbociclib 75 mg (n=3)
  • level 2: ibrutinib 420 mg and palbociclib 75 mg (n=3)
  • level 3: ibrutinib 420 mg and palbociclib 100 mg (n=6)
  • level 4: ibrutinib 560 mg and palbociclib 100 mg (n=10)
  • level 5: ibrutinib 560 mg and palbociclib 125 mg (n=5)

In each group, palbociclib was administered for 21 days of each 28-day cycle. Treatment continued until disease progression, unacceptable toxicity, or patient withdrawal.

During the trial, the median number of treatment cycles administered was 15 (range = 1-51), and nine patients are still receiving treatment as of study publication. The reasons for study withdrawal included:

  • disease progression (n=9)
  • allogeneic hematopoietic cell transplantation (n=4)
  • cytopenia (n=2)
  • elevated liver enzymes (n=1)
  • patient refused further treatment (n=1)
  • death unrelated to study treatment or MCL (n=1)

Level 4 (ibrutinib 560 mg and palbociclib 100 mg) was identified as the maximum tolerated dose of the study drugs, after researchers observed a dose-limiting toxicity of grade 3 rash in two patients enrolled in level 5. One additional dose-limiting toxicity, grade 4 neutropenia lasting longer than seven days, occurred at dose level 3.

Cytopenias were the most common grade 3-4 adverse events (AEs) observed in the entire study cohort (neutropenia, 41%; thrombocytopenia, 30%; anemia, 15%), followed by hypertension and febrile neutropenia.

The authors also identified several other “AEs of interest,” including one each of the following: grade 1 reactivation of viral hepatitis, grade 2 C. difficile infection, grade 3 varicella zoster viral encephalitis, grade 3 influenza A infection, and grade 3 atrial fibrillation.

Four patients across all dose levels required treatment interruptions, and eight required dose reductions, which the researchers noted were “mostly due to cytopenias.”

Two-thirds (18) of the patients (67%) had a partial response or better to treatment. This included 10 patients who experienced a complete response (37%).

Over a median follow-up of 25.6 months (range not reported), the rate of progression-free survival (PFS) and overall survival at two years were 59.4 percent and 60.6 percent, respectively. The investigators found no association between PFS and disease severity (per Mantle Cell International Prognostic Index score; p=0.222), Ki67 proliferation (p=0.359), or response to last therapy (p=0.262). Eleven patient deaths occurred during the study, most of which were related to MCL (n=9).

The overall response rate was similar to that reported in the phase II pivotal trial of single-agent ibrutinib, the authors noted, adding, “Although BTK inhibitor–based combinations appear promising, the degree to which they improve upon single-agent ibrutinib is unclear.”

Limitations of this early-phase study include its small patient cohort, the lack of randomization, and the lack of a comparator control.

An ongoing phase II study is evaluating the ibrutinib-palbociclib combination at the maximum tolerated dose identified in this trial. This phase II trial incorporates genetic profiling and functional assays of gene and protein expression “to have a better understanding of tumor- and patient-specific factors to better tailor treatment to individual patients.”

The authors report relationships with Janssen and Pharmacyclics, the manufacturers of ibrutinib.


Reference

Martin P, Bartlett NL, Blum KA, et al. A phase I trial of ibrutinib plus palbociclib in previously treated mantle cell lymphoma. Blood. 2019 January 28. [Epub ahead of print]

Ibrutinib is one of two BTK inhibitors approved by the U.S. Food and Drug Administration and has become a standard treatment option for patients with relapsed/refractory MCL, given its excellent single-agent activity and favorable toxicity profile. However, not all patients with relapsed/refractory MCL derive significant clinical benefit, as approximately one-third of patients do not achieve a response to the drug, and most patients experience disease progression within 10 to 18 months.

Combination strategies are being evaluated, including combinations with venetoclax, lenalidomide, and other targeted agents. As reported in this article, the combination of palbociclib, a CDK-4/6 inhibitor, with ibrutinib is appealing given previous observations. MCL is a lymphoid cancer characterized by dysregulation of the cell cycle, which can be inhibited by palbociclib’s ability to induce cell-cycle arrest.

While the molecular basis of ibrutinib resistance is unclear in MCL, palbociclib has been shown to sensitize ibrutinib-resistant cell lines to ibrutinib. This phase I trial demonstrated the safety of this combination and determined the recommended phase II dose, but it remains unclear if the activity of this novel combination will be superior to ibrutinib. A phase II study by the Alliance for Clinical Trials in Oncology is under way to help answer this question.

The biologic rationale behind this novel doublet is compelling and hopefully clinicians will have a new and active regimen in relapsed/refractory MCL in the near term.

John Kuruvilla, MD, FRCPC
Cancer Clinical Research Unit, Princess Margaret Cancer Centre
Toronto, ON

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