Ribociclib demonstrated excellent penetration of the blood-brain barrier, with unbound CSF and tumor concentrations measuring more than 5 times the necessary value for inhibition of CDK 4/6. Among the 12 patients, 9 experienced a more than 20% decrease in RB phosphorylation levels. Only one-third of patients (4 of 12) were diagnosed with histologic pseudoprogression after therapy.

Much of the groundwork in preclinical data using CDK 4/6 inhibitors in glioblastoma has been laid by researchers at the University of Virginia (UVA) Medical Center, Charlottesville.3,4 Benjamin Purow, MD, professor of neurology at the center, noted that ongoing results are promising, but CDK 4/6 inhibitors are just one small step in the quest for more personalized medicine in these patients. “Identifying who will benefit most will not be as simple as finding patients with CDK 4/6 overexpression. In vitro data [have] shown CDK 4/6 inhibitors are most potent in the proneural subtype of glioblastoma. Finding the best patients for this approach is still at the research level.”

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Dr Sanai indicated that while data on central nervous system penetration and early clinical responses are encouraging, the outcomes in single-agent regimens of CDK 4/6 inhibitors are not likely to be durable. “Monotherapy is highly unlikely to be effective due to the genetic heterogeneity and adaptation of the disease. With ribociclib therapy, at the time of recurrence, we could see a concomitant activation of the mTOR pathway. Our strategy is to identify agents that tackle the roadblock of the blood-brain barrier and modulate targets. We aim to build upon agents for multidrug cocktails, with CDK 4/6 inhibitors as the backbone. Our goal is to pursue multiple variants in parallel and find where the pharmacokinetics and pharmacodynamics have the best effects.”


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Combination therapy approaches are currently being studied that group CDK 4/6 inhibitors with mTOR and ERK inhibitors, as well as with selinexor.

Ongoing studies are centered on recurrent therapy. If studies continue to show promising results, Dr Sanai anticipates an expanded role for this approach. “At recurrence, there is no agreed-upon second line. Clearly there is a void to be filled. If we find anything to be effective as second-line therapy, it makes sense to continue the study as first line.”

References

  1. Tien A-C, Li J, Bao X, DeRogatis A, Kim S, Mehta S, Sanai N. A phase 0 trial of ribociclib in recurrent glioblastoma patients incorporating a tumor pharmacodynamic- and pharmacokinetic-guided expansion cohort. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-19-013
  2. Schettini F, De Santo I, Rea CG, et al. CDK 4/6 inhibitors as single agent in advanced solid tumors. Front Oncol. 2018;8:608.
  3. Olmez I, Brenneman B, Xiao A, et al. Combined CDK4/6 and mTOR inhibition is synergistic against glioblastoma via multiple mechanisms. Clin Cancer Res. 2017;23(22):6958-6968.
  4. Li M, Xiao A, Floyd D, et al. CDK4/6 inhibition is more active against the glioblastoma proneural subtype. Oncotarget. 2017;8(33):55319-55331.