Abstract
Background
Central nervous system (CNS) tumors are associated with considerable morbidity and high mortality. Cyclin-dependent kinases (CDKs) regulate cell division in cancer, and CDK4/6 inhibitors are used for the treatment of breast cancer, representing an attractive therapy for different tumor types.
Methods
Here, we report mature results of a multicenter basket trial exploring the CDK4/6 inhibitor abemaciclib in patients with recurrent CNS tumors, including patients with glioma, primary CNS lymphoma, meningioma, and ependymoma. We expanded our cohort of meningioma patients based on preliminary evidence for activity. Patients were treated with 200 mg oral abemaciclib twice daily for days 1–28, following FDA recommendations for breast cancer. Primary outcomes included radiographic response rates and progression-free survival (PFS) at 6 months post-treatment. We also evaluated overall survival (OS) and toxicity. Exploratory outcomes included next-generation sequencing of tumor biopsies.
Results
Most cohorts did not demonstrate activity with the exception of the cohort of patients with recurrent meningioma, including patients with grade 2 or 3 disease (19/22 meningioma patients). In that group, the median PFS was 15 months (95% CI: 6.5, not reached) and median OS was 32.9 months (95% CI: 10.7, not reached); the 6-month PFS was 68.2% (95% CI: 51.3%, 90.7%). All 22 patients were evaluable for radiographic response, showing stable disease in 16/22 (73%) and progressive disease in 6/22 patients (27%).
Conclusion
Our data suggest that abemaciclib improves PFS and OS in patients with advanced meningioma. The 6-month PFS with abemaciclib in this study (68.2%) exceeded RANO proposed benchmarks for activity (49%).
Trial registration
Keywords: abemaciclib, brain tumors, clinical trial, meningioma
Key Points.
We report a multicenter trial of abemaciclib in patients with recurrent/refractory CNS tumors in an innovative signal-finding basket format.
We observe improved PFS and OS following abemaciclib treatment in recurrent and refractory meningioma.
Importance of the Study.
We present a novel signal-finding basket design trial to explore the activity of the CDK4/6 inhibitor abemaciclib in patients with glioma, aggressive meningioma, and other primary brain tumors. In the meningioma cohort, which included patients with tumors with and without mutations in the gene encoding Neurofibromatosis type 2 (NF2), we observed improved progression-free and overall survival. Meningiomas are the most common adult primary intracranial tumor and are typically treated with surgery and/or radiotherapy. Systemic therapy options remain limited with no FDA-approved therapeutics for recurrent meningiomas refractory to surgery or radiation. Our study identifies CDK4/6 inhibition as a potential therapeutic strategy in aggressive meningioma.
Primary brain tumors represent an area of oncology in dire need of better medical therapies. Alterations in the cell cycle occur frequently in human cancers. The Retinoblastoma protein (pRb, encoded by RB1), a central tumor suppressor regulated by cyclin-dependent kinases (CDKs), inhibits DNA replication and cell proliferation through Early region 2 binding factor (E2F)-dependent transcriptional regulation.1 Except for tumors with functional loss of pRB which functions downstream of the CDK4 and CDK6—cyclin D1 complex, most cancers are potentially sensitive to pharmacologic inhibition of CDK4 and CDK6. Given the challenges in developing pRb-specific anticancer drugs, CDK inhibitors have emerged as an attractive therapeutic option to modulate the pRb pathway across multiple cancer types.
Among the available CDK4/6 inhibitors, abemaciclib has been studied extensively due to its potency and selectivity, as well as its efficacy in blocking tumor cell proliferation.2 In 2017, the FDA approved abemaciclib for the treatment of hormone-receptor positive and human epidermal growth factor 2 negative (HR + HER2-) breast cancer.3 From a therapeutic standpoint, the goal of inhibiting CDK4 and CDK6 with a small molecule is to prevent cell cycle progression through the G1 restriction point, thus arresting tumor growth. Thus, abemaciclib is an attractive therapeutic agent for a variety of cancers, including primary brain tumors.
The most common type of primary brain tumor needing chemotherapy at recurrence is a glioma, and whether malignant (WHO grade 3 and 4 gliomas) or low-grade (grade 2 gliomas), they are associated with a progressive and usually aggressive disease course. Other brain tumor types, such as meningioma and ependymoma, have no standard chemotherapeutic options at recurrence despite prior surgery and radiotherapy. Given the pancancer reliance on cell cycle dysregulation for growth, combined with abemaciclib penetration into the CNS, CDK inhibition with abemaciclib is an attractive potential therapeutic target for all CNS tumors.1
Multiple well-described genetic alterations can result in overactivity of the CDK pathway, and others may exist as well. In malignant gliomas, CDKN2A/B deletion is a common occurrence resulting in overactivity of the CDK4/6 and then downstream inhibition of RB1. However, given the clear differences between IDH-mutant and wildtype glioma, we separated these into distinct cohorts.
Additionally, we had particular interest in meningioma. The most common genetic alteration in meningiomas, and specifically aggressive meningiomas, is NF2 loss of function, either through inactivating point mutations in NF2 or through broad copy number loss of chromosome 22.4 The exact function of the role of NF2 deficiency remains unclear to date. One proposed function of NF2 in meningioma is the regulation of the tumor cell cycle through disinhibition of CDK4/6 and subsequent modulation of the pRb pathway.5
Meningioma is the most common primary brain tumor in adults with an estimated 37,000 new cases per year in the US.6 Of these, the majority are WHO grade 1, and only a small fraction are WHO grade 2 or 3.7 Many meningiomas are managed conservatively with surveillance imaging, and those in need of intervention are often treated successfully with first-line surgery or radiation. However, some grade 1 and most grade 2 and 3 meningiomas will grow and recur despite surgery or radiotherapy with estimates varying as high as 50–100% at 5 years for WHO grade 2 and 3 meningiomas, and even 7–47% for WHO grade 1 meningiomas.8
There are no FDA-approved treatments for recurrent meningioma, and many patients endure multiple craniotomies and courses of radiotherapy. While the NCCN guidelines suggest bevacizumab, sunitinib, bevacizumab combined with everolimus, and somatostatin analogues in certain circumstances,9 none have achieved a level of efficacy that would lead to FDA approval.
The landmark RANO-meningioma analysis of the literature on medical therapies for recurrent meningioma reviewed all the available experience on chemotherapies for meningioma.10,11 In the population of surgery- and radiotherapy-refractory meningioma, the estimated 6-month progression-free survival (PFS6) historical benchmarks to compare future trials were 38% for grade 2 and 3 meningiomas and 43.6% for grade 1 meningiomas. For studies evaluating patients with grade 2 and 3 meningiomas, the group suggested that a PFS6 rate of 49% or higher would be suggestive of a potentially active therapy.
Here, we report the results of our CNS basket trial with abemaciclib utilizing a novel trial design to discover new therapeutic strategies in various CNS tumors. The focus is on the meningioma cohort as our mature data demonstrate that the CDK4/6 inhibitor abemaciclib improves PFS, exceeding the RANO PFS6 threshold for experimental therapies in patients with advanced or recurrent meningioma. Our results support the use of abemaciclib in recurrent meningioma, where tumor control becomes challenging due to the scarcity of other effective therapeutic options.
Methods
Patients and Ethical Statement
This was a prospective, multicenter, investigator-initiated open-label nonrandomized CNS basket trial conducted at Memorial Sloan Kettering Cancer Center (New York, NY), Lehigh Valley Hospital (Allenton, PA), and Hartford Hospital (Hartford, CT) from November 2017 to June 2022. The study was approved by the Institutional Review Board of MSK and then each participating site, in agreement with the Declaration of Helsinki. MSK has a Federal Wide Assurance (FWA) with the Office of Human Research Protections (OHRP) in order to certify compliance with the regulations set forth at 45 CFR 46, 21 CFR parts 50, 56, 312, and 812 and the Privacy Rule at 45 CFR parts 160 and 164. This trial was registered in ClinicalTrials.gov with ID NCT03220646 (https://classic.clinicaltrials.gov/ct2/show/NCT03220646). All research participants were required to provide written informed consent.
Study Design
The study utilized a novel “basket trial” design to explore the efficacy of abemaciclib in various CNS tumors with the ability to expand certain cohorts if there were signs of activity. The trial consisted of five cohorts (Figure 1A). Cohort A consisted of recurrent IDH wildtype grade 2 and 3 gliomas, Cohort B consisted of patients with any grade recurrent glioma who were planned for standard of care surgical resection; they received preoperative and postoperative abemaciclib, and Cohort C consisted of three sub-cohorts including C1 (recurrent IDH-mutant glioma), C2 (recurrent meningioma), and C3 (“other” consisting of any other recurrent primary CNS tumor) (Figure 1B).
Figure 1.
A CNS basket trial to assess abemaciclib in recurrent brain tumors. (A) Overall study design. (B) CONSORT diagram. (C) Clinical Benefit Rate. Shown is the percentage of Complete Responses + Partial Responses + Progression Free Survival at 6 months (CR + PR + PFS6) across all cohorts
Eligibility
Patients enrolled were required to have: recurrent IDH wild type grade 2 or 3 glioma (cohort A), recurrent glioma planned for standard-of-care resection (cohort B), recurrent IDH-mutant glioma (cohort C1), either histologically proven grade 1–3 meningioma or classic radiographic features of a meningioma but for which surgical resection was not advised and that were recurrent or progressive (cohort C2), or any other recurrent primary brain tumor without a known effective therapy (cohort C3) (Figure 1B). There was no limit on the number of prior recurrences or prior therapies. Patients were required to be ≥ 18 years old, have a KPS ≥ 60, and be willing and able to swallow pills. Baseline screening laboratory values required hemoglobin ≥ 8 g/dL without transfusion, platelet count ≥ 100 × 109/L, absolute neutrophil count (ANC) ≥ 1.5 × 109/L without growth factor support, total bilirubin ≤ 1.5 x upper limit of normal (ULN), AST/SGOT and/or ALT/SGPT ≤ 3 x ULN, and serum Creatinine ≤ 1.5 x ULN. Patients had to be on a stable dose of corticosteroids ≥ 5 days prior to baseline MRI. Before starting the study treatment, patients must have recovered from any toxic effects of prior therapies (except for residual alopecia or Grade 2 peripheral neuropathy). Regarding prior lines of treatment, at least 3 weeks must have elapsed from the completion of any signaling pathway modulators, > 3 weeks since temozolomide, > 4 weeks since carboplatin or cisplatin, and > 6 weeks from nitrosoureas (eg, BCNU, CCNU). In general, at least 4 weeks must have elapsed from any other anticancer drug therapy (eg, bevacizumab).
Patients were excluded from the study if there was radiographic evidence of significant intracranial hemorrhage. Patient must not have received prior CDK inhibitor therapy. Patients could not have a serious preexisting medical condition(s) or uncontrolled intercurrent illness that would preclude participation in this study, psychiatric illness/social situations that would limit compliance with study requirements, other active concurrent malignancy, or gastrointestinal illness that would cause diarrhea or limit investigational agent absorption. Patients must not have been taking enzyme-inducing antiepileptic drugs.
For the glioma cohorts, patients with known RB1 mutations were excluded. For the meningioma cohort, the influence of genetic markers is largely unknown. Given the uncertainty around the role of the NF2 gene, we did not restrict this study cohort to NF2-deficient meningiomas, and patients were eligible regardless of genetic alterations. We collected molecular data where available for clinical purposes as an exploratory analysis.
Treatment Plan
All patients received 200mg oral abemaciclib monotherapy twice daily on days 1–28 of a 28-day cycle, the FDA-approved monotherapy dose for breast cancer. Treatment continued until either disease progression, unacceptable toxicity, withdrawal of consent, or if the treating physician decided it was in the patient’s best interest to withdraw. The dose of abemaciclib was reduced to 150 mg and then 100 mg for patients who experienced a treatment-related grade 3 or higher non-hematologic toxicity (excluding diarrhea, ALT elevation, or pneumonitis for which separate criteria were applied, or alopecia or fatigue) or grade 4 or recurrent grade 3 hematologic toxicity. Disease assessments were performed with MRI and clinical exam every two cycles. Responses were determined using standard RANO criteria, as the RANO Meningioma guidelines were published in 2018, a year after our study opened to accrual.12 Pathology for eligibility and radiographic response assessments were determined locally, central confirmation was needed for PR or CR. Treatment-related toxicities were evaluated using the most updated National Cancer Institute Common Terminology Criteria.
Statistical Considerations
The IDH wildtype astrocytoma study cohort (cohort A) was designed as the primary statistical cohort, and the others were designed for descriptive analysis with radiographic response rate, median PFS, 6-month progression-free survival (PFS6), OS, and toxicity (all patients who received at least one dose of study drug were included in the toxicity assessment). The PFS time is defined as the number of months from the treatment start date until the first disease progression or patient death if known; otherwise, it is defined as the time until the date of last follow-up. The OS time is defined as the time in months until patient death or the last known date of follow-up. The survival outcomes of interest—including 2-year OS, 6-month and 2-year PFS, along with their corresponding 95% confidence intervals (CIs)—were estimated using the Kaplan-Meier method in the11 package in R (v4.4.1). Estimates for the median survival times and their 95% CI were also calculated using the {gtsummary} package.
As an exploratory component in the meningioma cohort, patients who had next-generation sequencing (NGS) of their tumors as part of their clinical care had their NGS results reviewed and assessed for correlation with clinical outcomes, with particular attention to components of the CDK pathway and NF2 deficiency either by inactivating point mutations or chromosome 22 loss. Subsequent analysis using the log-rank test was performed to compare the PFS between patients with or without an NF2 deficiency.
Results
The distribution of patients among the cohorts is seen in Figure 1A–B. All patients are off treatment in this fully mature dataset. Cohort A enrolled 9 patients with IDH-wildtype astrocytomas (eight grade 3 and one grade 2). Cohort B enrolled 12 patients, including 7 IDH wildtype GBM, 4 IDH-mutant grade 3 astrocytoma, and 1 IDH-wildtype grade 2 astrocytoma. Cohort C1 enrolled 10 patients with IDH-mutant gliomas (4 astrocytoma, 5 oligodendroglioma, and 1 GBM). Cohort C2 initially enrolled 10 meningiomas (one grade 1, six grade 2, and three grade 3) (Figure 1B).
Glioma Cohorts and Initial Evaluation
Cohort A enrolled 9 patients with IDH-wildtype gliomas. All patients in this cohort came off treatment rapidly, with only 2 patients remaining on treatment after the first disease assessment, and only 1 patient was without progression at the 6-month timepoint. Cohort B enrolled any glioma that was going for surgery, and similarly, only 3 patients in this cohort were without progression at 6 months. Cohort C1 enrolled 10 patients with IDH-mutant gliomas. Even in this cohort with only IDH-mutant patients, progression was rapid in the majority of patients with only 2 patients remaining progression-free at the 6-month timepoint.
At this point, the lack of response seen in these glioma patients along with similar outcomes in other studies, we evaluated the data and decided to only enroll further patients to the meningioma cohort. We reviewed the Clinical Benefit Rate (CBR) defined as CR + PR + PFS6 for each cohort, and the meningioma cohort was the only one that was reasonable for expansion given the historical data in those diseases (Figure 1C). CBR was selected because it would be the most inclusive of potential antitumor effect especially in diseases where stabilization is considered a successful outcome in addition to radiographic responses (CR + PR).13 Therefore, using CBR as a preliminary cohort evaluation tool, we would be least likely to discontinue enrollment to any cohort for perceived inactivity prematurely if in fact there was the potential for benefit (essentially looking for any sign of benefit). However, in all the glioma patients (cohorts A, B, and C1) only 1 PR was seen, and it was in a patient who was also progression-free at 6 months.
Cohort C2—Meningioma
Patient Characteristics
A total of 22 patients with recurrent/progressive meningiomas were enrolled in the meningioma cohort, including 2 grade 1 meningioma, 11 grade 2 meningioma, 8 grade 3 meningioma, and 1 unknown tumor grade (no prior surgery but on posttreatment resection pathology was grade 2). Patients had a median age of 67 (range 39–77). All but one patient had prior surgery, and all patients had prior radiotherapy, and additionally 6 patients had received prior chemotherapy. Of the 6 patients who received prior chemotherapy, only one patient received bevacizumab prior to enrollment and that patient stopped bevacizumab 11 months prior to enrollment. Radiotherapy was administered a median of 30.5 months prior to study enrollment (range 9.1–157.8 months). Patients were heavily pretreated with a median number of 3.5 prior therapies (range 1–11) (Table 1). Eleven patients had MR-perfusion imaging available at baseline and all 11 patients had hyperperfusion in the target recurrent meningioma lesion.
Table 1.
Cohort C2/Recurrent Meningioma Patient Characteristics (n = 22)
| Sex | |
| Male | 16 |
| Female | 6 |
| Median Age (range) | 67 years (39–77) |
| Median KPS (range) | 80 (60–100) |
| Histology (n) | |
| WHO grade 1 meningioma | 2 |
| WHO grade 2 meningioma | 11 |
| WHO grade 3 meningioma | 8 |
| Unknown | 1 |
| Median number of prior treatments (range) | 3.5 (1–11) |
| Prior surgery (n) | 21 |
| Prior radiation (n) | 22 |
| Median time from prior radiation | 30.5 months (range 9.1–157.8) |
| Prior chemotherapy (n) | 6 |
| Prior bevacizumab (n) | 1 |
Response Assessments and Primary Outcomes
The median PFS in the meningioma cohort (N = 22) was 15 months (95% CI: 6.5, not reached), and median OS was 32.9 months (95% CI: 10.7, not reached) (Figure 2A, B). The PFS6 was 68.2% (95% CI: 51.3, 90.7). The 2-year PFS was 38.6% (95% CI: 22.3, 66.8) and the 2-year OS was 63.0% (95% CI: 39.4, 79.5). Of note, there were two grade 1 meningiomas included in this cohort, and one unknown grade who had a grade 2 meningioma on post-treatment resection, and one of the grade 1 patients progressed after only one month of therapy. In the 19 patients with recurrent WHO grade 2 and 3 meningiomas, the median PFS was 20 months (95%CI: [6.5, not reached]) and the PFS6 was 68% (95%CI: [50%, 93%]) (Figure 2A, B).
Figure 2.
Clinical course of patients treated with Abemaciclib. (A) Impact of abemaciclib on Progression-free survival and overall survival in recurrent WHO Grade 2 and 3 Meningiomas (n = 19); in red, current study metrics; in black, historic benchmarks for comparison; (B) Swimmers Plot of the entire Meningioma cohort C2 (n = 22); (C) Genomic evaluation of patients with available next-generation sequencing data (n = 10). *=censored patients (1 off to pursue surgery and 1 off because of the need for prohibited concomitant medication).
All of the 22 patients were evaluable for radiographic response. No patient achieved a complete or partial response. The best radiographic response was stable disease in 16/22 patients (73%) and progressive disease in 6/22 patients (27%).
Toxicities
Overall, abemaciclib was well tolerated in this patient population. In the total meningioma cohort (N = 22), no grade 4 or 5 toxicities were seen, and few grade 3 toxicities occurred (Table 2). Of note, frequent grade 1 and 2 toxicities included diarrhea (14), fatigue (12), thrombocytopenia (7), anemia (5), Creatinine increases (4), leukopenia (4), and nausea (3). 3/22 patients (13.6%) withdrew consent for multiple grade 1 and 2 toxicities (especially fatigue and diarrhea) that interfered with their quality of life.
Table 2.
Toxicity Observed in All Meningioma Patients Receiving at least One Dose of Study Drug (N = 22)
| Toxicity | Grade 1 (n) | Grade 2 (n) | Grade 3 (n) |
|---|---|---|---|
| Anemia | 1 | 4 | 1 |
| Fatigue | 5 | 7 | 1 |
| Febrile neutropenia | 1 | ||
| Neutropenia | 1 | ||
| Alanine aminotransferase increased | 1 | ||
| Alopecia | 2 | 1 | |
| Anorexia | 3 | 1 | |
| Creatinine increased | 3 | 1 | |
| Diarrhea | 13 | 1 | |
| Headache | 1 | 1 | |
| Lymphopenia | 1 | 1 | |
| Nausea | 2 | 1 | |
| Rash—maculopapular | 2 | 1 | |
| Leukopenia | 2 | 2 | |
| Abdominal pain | 1 | ||
| Aspartate aminotransferase increased | 1 | ||
| Constipation | 2 | ||
| Dysgeusia | 1 | ||
| Dyspepsia | 1 | ||
| Dyspnea | 1 | ||
| Edema—limbs | 1 | ||
| Hyperkalemia | 1 | ||
| Mucositis—oral | 2 | ||
| Myalgia | 1 | ||
| Thrombocytopenia | 7 | ||
| Pruritus | 2 | ||
| Vomiting | 1 |
In the overall study population (n = 63), abemaciclib was also well tolerated with no grade 4 or 5 toxicities. Grade 3 AEs deemed at least possibly related to investigational therapy included anemia (n = 1), diarrhea (n = 1), fatigue (n = 3), febrile neutropenia (n = 3), neutropenia (n = 3), vomiting (n = 1), and leukopenia (n = 1).
Exploratory Outcomes
NGS data were available for 10/22 patients, and we detected alterations in the CDK pathway (including CDKN2A, CDKN2B, and CDKN1B deficiencies) in 4 patients (40%). No genetic correlations could be established with clinical outcomes, likely due to the small number of patients. Similarly, of the 10 patients with results regarding the tumor NF-2 status, 8/10 (80%) had NF2 alterations, and significant correlations with clinical outcomes could not be established (Figure 2C). Of note, one of the NF2-intact patients with recurrent anaplastic meningioma remained on treatment for 22.3 months and radiographically showed disease stabilization of a previously growing tumor.
Stable disease in meningiomas can sometimes be misleading if the tumors are only growing very slowly before trial enrollment and then continue to grow slowly until they eventually hit the threshold for disease progression. In order to better understand the impact of stable disease, we evaluated tumor volume both pretreatment and then posttreatment for patients who both had scans available and were evaluated with MRI scans (as opposed to CT scans). Figure 3 demonstrates the volume curves in the 15 patients available for this analysis.
Figure 3.
Tumor control by Abemaciclib treatment in patients with NF-altered or NF-intact tumors. (A) Left, example of tumor control following abemaciclib treatment demonstrated in a patient with NF2 deficiency; right, tumor volume growth on MRI imaging, pre- and post-abemaciclib treatment (start of treatment indicated with a dotted red line) for this same patient, corresponding to the same patient and plotted in the swimmers plot in Figure 2 (Swim ID #11). (B) Longitudinal tumor volume growth on MRI imaging, pre- and post-abemaciclib treatment (start of treatment indicated with a dotted red line). Graphs correspond to patients with available pre- and/or post-abemaciclib treatment, and the same patients are plotted in the swimmers plot in Figure 2 (Swim ID # indicated in each graph). Times from radiation treatment (RT) or prior bevacizumab (BEV) are indicated in each graph, as well as baseline MR-perfusion imaging results.
Cohort C3—Any Recurrent Primary Brain Not Eligible for Other Cohorts
This cohort enrolled 10 patients with various CNS tumors that were recurrent (Table 3). Of note, 3 patients with ependymomas were enrolled, and the two with a myxopapillary ependymoma remained on therapy with prolonged stabilization for over two years. There were also 3 primary CNS lymphoma patients enrolled, but no activity was seen. One patient with recurrent pituitary carcinoma had stable disease for 20.2 months.
Table 3.
Cohort C3—Any Other Recurrent Primary Brain Tumor
| Patient | Histology | PFS (months) | Best ORR |
|---|---|---|---|
| 1 | Myxopapillary Ependymoma | 29.1 | SD |
| 2 | Anaplastic Ependymoma | 0.8 | PD |
| 3 | Myxopapillary Ependymoma | 25.8* | SD |
| 4 | Diffuse Midline Glioma -WHO grade 4 | 2.1 | PD |
| 5 | Glioneuronal Rosette Forming Tumor | 5.7 | SD |
| 6 | PCNSL | 1.2 | PD |
| 7 | PCNSL | 1.5 | PD |
| 8 | PCNSL | 1.2 | PD |
| 9 | Pituitary Adenoma | 1.9 | PD |
| 10 | Pituitary Carcinoma | 20.2 | SD |
*= Withdrew, time of censoring.
Discussion
We report an investigator-initiated “CNS-basket trial” to uncover signals of potential antitumor activity of abemaciclib in patients with different types of recurrent primary brain tumors. Given the prominent role of cell cycle deregulation in the pathogenesis of human cancer,14,15 we felt that inhibitors of CDK4/6 would be an appealing choice to explore this “signal-finding” clinical trial design. There are multiple CDK4/6 inhibitors under consideration as anticancer agents15,16 and we selected abemaciclib due to its reported penetration across the blood–brain barrier.17–19 We tested abemaciclib at its FDA-approved dosing regimen and found it to be generally well tolerated. Nonetheless, many patients experienced at least some grade 1 and 2 adverse events, and three patients elected to withdraw from the trial without meeting predefined study criteria for disease progression. However, overall abemaciclib was associated with few grade 3 adverse events and no grade 4 or 5 adverse events.
Our initial focus was on patients with adult-type diffuse glioma, the most common type of malignant primary brain tumor in adults, but we were discouraged by the lack of activity in the first nine patients and closed this patient cohort. The apparent lack of clinical activity of abemaciclib against IDH-wildtype astrocytoma/glioblastoma is consistent with the result of other trials.20 We also did not observe preliminary signs of antitumor activity in our cohort of patients with IDH-mutant glioma cohort, which fully accrued. Hence, we did not expand this trial cohort either.
In contrast to our observations in the glioma cohorts, we observed preliminary signs of clinical activity in our cohort of meningioma patients (n = 22). Abemaciclib demonstrated an encouraging PFS-6 rate of 68.2%, even if we include only the WHO grade 2 and 3 patients, in which the PFS-6 rate remained at 68.0%, far exceeding the RANO-proposed bar for active therapies (Figure 2). Of note, due to the specific timelines of the present study, which opened to accrual in 2017, we used RANO instead of RANO Meningioma guidelines, which were released a year later. However, since we used PFS-6 as the main endpoint against historical benchmarks, it was not necessary to amend the study to use a different criteria, given the lack of impact on our study.
Stable disease can often be misleading in the meningioma literature because many of these tumors are slow-growing and would eventually hit the threshold for PD given enough time. Similarly, PFS-6 can be misleading for the same rationale, which the recent RANO review attempts to consider and correct for with the high bar set for potentially active treatments. However, we propose that our trial cohort of meningioma patients included a true treatment-refractory population and not a slow-growing cohort that simply took a longer time to progress. Although eligibility for trial required recurrence/progression as defined by RANO criteria, which maintains the trial’s interpretation within the context of the prior literature, post hoc, we attempted to fully investigate this cohort to confirm abemaciclib activity in this group. In regard to patient characteristics, nearly all patients presenting higher grade pathologies, refractory disease, a median of 30.5 months elapsed since the prior radiation, and prior chemotherapies only included one patient who received prior bevacizumab. We evaluated pretreatment MRI scans where available in order to evaluate pretreatment growth volumes and compare them with posttreatment growth volumes, demonstrated in Figure 3. Additionally, we reviewed MR-perfusion where available and found that 11/11 patients demonstrated hyperperfusion in their recurrent tumors. By evaluating these confounders and attempting to exclude that these recurrences were pseudoprogression, we propose that these data further support the potential activity of the drug in this disease. The growth curves in Figure 3 highlight the substantial impact of disease stabilization in this population and help demonstrate the activity of the drug, and we propose that future trials incorporate the pretreatment analysis as a requirement in order to fully assess any drug’s impact in this disease.
Molecular assessment of the tumor tissue was feasible for a subset of meningioma patients enrolled in our trial. 8/10 patients harbored NF-2 alterations; 2/10 patients did not harbor any NF-2 alterations. Of the two patients without NF2 deficiency, one remained on abemaciclib for almost two years with a rapidly growing anaplastic meningioma that stabilized. The other patient without NF2 alteration withdrew consent after cycle 2 without radiographic or clinical evidence for disease progression. The tumor from the latter patient also harbored a CDKN2A deletion, a known negative prognostic marker in meningioma.21
Cohort C also included patients with a collection of other CNS histologies (Table 3). Although only three patients with PCNSL were accrued, none of the three achieved a response and rapidly came off trial. Targeted agents such as BTK inhibitors have been active in this disease with response rates as high as 74% with ibrutinib.22,23 Despite the very small sample of 3 patients with PCNSL in our study, we consider it unlikely that abemaciclib is a very active agent in PCSNL.
We also treated three patients with ependymoma and observed prolonged disease stabilization in two patients with myxopapillary ependymoma, a rare and distinct subtype of spinal cord ependymomas with typically slow tumor growth. Given the typically indolent biology of these tumors and their rarity, we did not expand the trial for this tumor type and cannot comment further on the activity of abemaciclib in this disease.
Patients with recurrent primary brain tumors, and in particular rare primary brain tumors, rarely have an opportunity to participate in clinical trials with novel agents and, in most cases, there are no FDA-approved therapies with documented antitumor activity. To address this formidable challenge to clinical drug development in neuro oncology, we explored a novel clinical trial disease which we termed “CNS-basket” trial. Unlike most other “basket trials,” our clinical trial did not restrict enrollment to a particular tumor genotype.24–26 The current trial, and specifically the meningioma results, are limited by similar factors affecting most meningioma trials, including small sample size and nonrandomized design relying on comparison to historical benchmarks. Despite the limitations of our trial, we were able to identify a preliminary signal of activity of abemaciclib in recurrent and treatment-refractory meningioma. Further prospective, randomized trials with CDK4/6 inhibitors in aggressive meningioma seem warranted.
Acknowledgments
This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748 and R35 NS105109 to IKM; funding and drug provided by Eli-Lilly.
Contributor Information
Thomas J Kaley, Department of Neurology, Weill Cornell Medical College, New York, New York, USA; Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Christian Grommes, Department of Neurology, Weill Cornell Medical College, New York, New York, USA; Human Oncology and Pathogenesis Program, Sloan Kettering Institute, New York, NY, 10065, USA; Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Elizabeth Coffee, Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Robert J Young, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Tara Morrison, Lehigh Valley Hospital-Cedar Crest, Allentown, PA, USA.
Ahmad Daher, Hartford HealthCare Cancer Institute, Plainville, CT, USA.
Lauren R Schaff, Department of Neurology, Weill Cornell Medical College, New York, New York, USA; Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Yufei Deng, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Subhiksha Nandakumar, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Eli L Diamond, Department of Neurology, Weill Cornell Medical College, New York, New York, USA; Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Lisa M DeAngelis, Department of Neurology, Weill Cornell Medical College, New York, New York, USA; Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Katherine S Panageas, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Igor Gavrilovic, Department of Neurology, Weill Cornell Medical College, New York, New York, USA; Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Andrew Lin, Department of Neurology, Weill Cornell Medical College, New York, New York, USA; Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Elena Pentsova, Department of Neurology, Weill Cornell Medical College, New York, New York, USA; Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Jacqueline Stone, Department of Neurology, Weill Cornell Medical College, New York, New York, USA; Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Bianca D Santomasso, Department of Neurology, Weill Cornell Medical College, New York, New York, USA; Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Anna F Piotrowski, Department of Neurology, Weill Cornell Medical College, New York, New York, USA; Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Suresh Nair, Lehigh Valley Hospital-Cedar Crest, Allentown, PA, USA.
Nikolaus Schultz, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA; Human Oncology and Pathogenesis Program, Sloan Kettering Institute, New York, NY, 10065, USA; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Anne S Reiner, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Ingo K Mellinghoff, Department of Neurology, Weill Cornell Medical College, New York, New York, USA; Human Oncology and Pathogenesis Program, Sloan Kettering Institute, New York, NY, 10065, USA; Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Author Contributions
Manuscript writing: TJK and IKM, with input, edits, and approval from all other authors. Data analysis and interpretation: TJK, KSP, ASR, SN, with input from all other authors. Statistical analysis and data interpretation: TJK, KSP, ASR, SN. Funding and project overview: TJK, IKM
Conflict of interest statement. TJK reports other support from Servier, unrelated to the present work. IKM reports researcher fees from Servier, Erasca, Abbvie, Roche, and Global Coalition for Adaptive Research, speaker fees from Baptist Health Care, and grants from Indiana University School of Medicine, and advisory board fees from Tango Therapeutics and Pathos Inc, all of them independent of the submitted work. AL reports institutional funding from Bristol Myers Squibb, unrelated to the present work. RJY reports equity in Agios, and consulting fees from Guerbet, ICON plc, NordicNeuroLab, Olea Medical, RadMD, Servier, and Turing Medical, unrelated to the present work. CG reports honoraria from Scripps Health; consulting or advisory roles from BTG, Kite/Gilead, Ono Pharmaceutical, Roche, Curis; speakers’ bureau from Ono Pharmaceutical; travel, accommodations, and expenses from Ono Pharmaceutical, Bayer, Bristol Myers Squibb, Pharmacyclics, Celgene, unrelated to the present work. LMD reports participation in a Global Advisory Panel for the Provincial Health Services Authority for the British Columbia Ministry of Health. No disclosures were reported by the other authors of the study.
Data Availability
Due to patient privacy restrictions, patient data and protected health information from this study are not publicly available. Trial results are posted in ClinicaTrials.gov. Deidentified genomics sequencing data from the present study will be publicly shared through cBioportal (https://www.cbioportal.org/). All other data will be made available upon reasonable request from a qualified medical or scientific professional for the specific purpose laid out in that request and may include deidentified individual and/or pooled participant data. The data for this request will be available after a data access agreement has been signed.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Due to patient privacy restrictions, patient data and protected health information from this study are not publicly available. Trial results are posted in ClinicaTrials.gov. Deidentified genomics sequencing data from the present study will be publicly shared through cBioportal (https://www.cbioportal.org/). All other data will be made available upon reasonable request from a qualified medical or scientific professional for the specific purpose laid out in that request and may include deidentified individual and/or pooled participant data. The data for this request will be available after a data access agreement has been signed.