Waterfall plot showing best tumor response in patients treated with palbociclib.
eFigure. CONSORT diagram
eTable. Incidence of Grade 2-4 adverse events
Customize your JAMA Network experience by selecting one or more topics from the list below.
Dickson MA, Schwartz GK, Keohan ML, et al. Progression-Free Survival Among Patients With Well-Differentiated or Dedifferentiated Liposarcoma Treated With CDK4 Inhibitor Palbociclib: A Phase 2 Clinical Trial. JAMA Oncol. 2016;2(7):937–940. doi:10.1001/jamaoncol.2016.0264
More than 90% of well-differentiated or dedifferentiated liposarcomas (WD/DDLS) have CDK4 amplification. The selective CDK4 and CDK6 inhibitor palbociclib inhibits growth and induces senescence in liposarcoma cell lines and xenografts. Our prior phase 2 study demonstrated that treatment with palbociclib (200 mg daily for 14 days every 21 days) resulted in clinical benefit in WD/DDLS but moderate hematologic toxic effects. It is important to understand whether palbociclib at a new dose and schedule—125 mg daily for 21 days every 28 days—results in clinical benefit and manageable toxic effects.
To determine the progression-free survival (PFS) at 12 weeks of patients with WD/DDLS treated with palbociclib (PD0332991).
Design, Setting, and Participants
In this phase 2, nonrandomized, open-label clinical trial conducted at the Memorial Sloan Kettering Cancer Center, 60 patients 18 years and older with advanced WD/DDLS and measurable disease by RECIST 1.1 were enrolled from December 2011 to January 2014 and followed to March 2015. Patients received oral palbociclib at 125 mg daily for 21 days in 28-day cycles.
Main Outcomes and Measures
Primary end point was PFS. Secondary end points included response rate and toxic effects.
Overall, 30 patients were enrolled in the initial cohort and 30 more in an expansion cohort. Median (range) age was 61.5 (35-87) years; 31 patients (52%) were male; median (range) Eastern Cooperative Oncology Group score was 0 (0-1). Progression-free survival at 12 weeks was 57.2% (2-sided 95% CI, 42.4%-68.8%), and the median PFS was 17.9 weeks (2-sided 95% CI, 11.9-24.0 weeks). There was 1 complete response. Toxic effects were primarily hematologic and included neutropenia (grade 3, n = 20 [33%]; grade 4, n = 2 [3%]) but no neutropenic fever.
Conclusions and Relevance
In patients with advanced WD/DDLS, treatment with palbociclib was associated with a favorable PFS and occasional tumor response. This dose and schedule appears active and may have less toxic effects than 200 mg for 14 days.
clinicaltrials.gov Identifier: NCT01209598
Well-differentiated or dedifferentiated liposarcoma (WD/DDLS) is one of the most common types of soft tissue sarcoma.1 Chemotherapy has minimal activity, and other than surgery, there are limited options for patients with recurrent disease.2 Recent work has identified the oncogene cyclin-dependent kinase 4 (CDK4) as a potential therapeutic target since it is highly amplified in greater than 90% of WD/DDLS.3-6
Palbociclib is a potent oral inhibitor of CDK4 and CDK6 that prevents downstream phosphorylation of the retinoblastoma protein.7,8 Palbociclib inhibits the growth of CDK4-amplified liposarcoma cell lines and xenograft models.9 We previously performed a phase 2 study that demonstrated that treatment with palbociclib (200 mg daily for 14 days every 21 days) results in clinical benefit in patients with advanced WD/DDLS but moderate hematologic toxic effects.10 Thirty patients were enrolled, and the median progression-free survival (PFS) was 18 weeks. Aiming to reduce toxic effects, we conducted a phase 2 study to assess PFS and toxic effects with palbociclib (PDO332991) at a new dose and schedule: 125 mg daily for 21 days every 28 days.
This was a nonrandomized, open-label phase 2 study performed at a single institution. The primary end point was PFS at 12 weeks; PFS at 12 weeks greater than 60% was considered promising and PFS less than 35% was considered not promising. With a 1-stage design, the study would be positive if at least 14 of the first 28 patients were progression-free at 12 weeks, with a type I error of 0.07 and type II of 0.10.11 After the initial cohort completed accrual, the study was extended to include additional patients in an expansion cohort to learn more about the activity of palbociclib in WD/DDLS and to obtain tumor biopsies.
Question What is the effect of treatment with palbociclib, a selective CDK4 inhibitor, in patients with well-differentiated or dedifferentiated liposarcoma?
Findings In this nonrandomized, open-label phase 2 study that included 60 patients, the progression-free rate at 12 weeks was 57%, and treatment was well-tolerated with primarily hematologic toxic effects.
Meaning Treatment with palbociclib is associated with favorable progression-free survival and occasional tumor response in patients with advanced liposarcoma.
Eligible patients were patients 18 years and older with advanced WD/DDLS, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and measurable disease by RECIST 1.1.12 In the initial cohort, patients must have received at least 1 prior systemic treatment; however, this was not required in the expansion cohort. In the initial cohort, patients were required to have CDK4 amplification by fluorescence in situ hybridization and retinoblastoma protein expression by immunohistochemistry. (The methods and criteria were described previously.10) Since CDK4 amplification is highly prevalent, all of the patients were positive. Thus the requirement for testing was removed for patients in the expansion cohort.
The protocol was approved by the institutional review board of Memorial Sloan Kettering Cancer Center and all patients provided written informed consent.
Patients were treated with 125 mg of palbociclib once daily for 21 days every 28 days. If a cycle had to be delayed by more than 7 days or grade 4 hematologic toxic effects occurred, the dose was reduced to 100 mg, then 75 mg.
Clinical examinations and laboratory testing were performed at the start of each 28-day cycle for the first 12 cycles, then every other cycle. Tumor response was assessed by a reference radiologist by computed tomography (CT) scan every 6 weeks for 36 weeks, then every 12 weeks. Toxic effects were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.13
Between December 2011 and April 2013, 30 patients were enrolled in the initial cohort. One patient withdrew consent and was inevaluable for response or PFS. Between April 2013 and January 2014, an additional 30 patients were enrolled in the expansion cohort (eFigure in the Supplement).
In total 60 patients were treated with palbociclib. All were included in the analysis of safety and adverse events. One patient was inevaluable for response and thus 59 evaluable patients were included in the analysis of response and PFS. The characteristics of all 60 patients enrolled are shown in the Table. The primary site of disease was the abdomen and retroperitoneum for 58 patients (97%) and 47 patients (78%) had dedifferentiated disease. Median (range) age was 61.5 (35-87) years, 31 patients (52%) were male, and median (range) ECOG score was 0 (0-1). All patients in the initial cohort had received at least 1 prior systemic treatment; however, in the expansion cohort 22 patients (73%) had received no prior systemic treatment. The prior treatments included doxorubicin or liposomal doxorubicin (n = 8), doxorubicin and ifosfamide (n = 6), gemcitabine (n = 5), gemcitabine and docetaxel (n = 13), MDM2 inhibitors (n = 3), and other drugs (n = 11). All of the patients in the initial cohort had CDK4 amplification. In the expansion cohort, 5 patients had CDK4 amplification, and the rest were not tested.
The incidence of grade 2 to 4 adverse events possibly, probably, or definitely attributed to palbociclib is shown in the eTable in the Supplement. The most common toxic effects were neutropenia (grade 3, n = 20 [33%]; grade 4, n = 2 [3%]), anemia (grade 3, n = 13 [22%]), and thrombocytopenia (grade 3, n = 3 [5%]; grade 4, n = 1 [2%]). Despite the frequency of neutropenia, there were no episodes of neutropenic fever.
Only 3 patients (5%) required dose reduction to 100 mg, and only 1 patient (1.7%) required a second dose reduction to 75 mg, all cases owing to hematologic toxic effects. Serious nonhematologic toxic effects were very rare.
In the initial cohort, 14 of the first 28 patients were progression free at 12 weeks. Thus, the study met its primary end point (Figure 1). The overall PFS at 12 weeks was 57.2% (2-sided 95% CI, 42.4%-68.8%). The median PFS was 17.9 weeks (2-sided 95% CI, 11.9-24.0 weeks).
The best response by RECIST for 57 evaluable patients is shown in Figure 2. There was 1 complete response lasting over 2 years. Two patients did not have follow-up CT scans on study due to clinical deterioration. There was no significant difference in PFS between patients who had or had not received prior systemic therapy (P = .70).
We previously demonstrated that treatment with palbociclib at the 200 mg dose for 14 days every 21 days was associated with favorable PFS and occasional responses in WD/DDLS. The current study confirms those results. Palbociclib was generally well tolerated with asymptomatic reversible neutropenia as the most common adverse effect. The median PFS at the 125 mg dose was 18 weeks, comparable to the 18 weeks reported in the trial of the 200 mg dose.10 We note that the 125 mg dose has since been approved by the US Food and Drug Administration for breast cancer and is commercially available.
Nine patients in the expansion cohort underwent paired tumor sample biopsies. The results of these biopsies showed that a clinical benefit from palbociclib treatment was associated with down-regulation of MDM2 mediated by ATRX.14 These data will be crucial to establishing a potential biomarker which could predict which patients may benefit from CDK4 inhibitors.
In patients with advanced well-differentiated or dedifferentiated liposarcoma, treatment with palbociclib is associated with favorable PFS, manageable toxic effects, and occasional tumor responses.
Corresponding Author: Mark A. Dickson, MD, Memorial Sloan Kettering Cancer Center, 300 E 66 St, New York, NY 10065 (email@example.com).
Accepted for Publication: January 27, 2016.
Published Online: April 28, 2016. doi:10.1001/jamaoncol.2016.0264.
Author Contributions: Dr Dickson had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Dickson, Schwartz, Qin, Singer, Tap.
Acquisition, analysis, or interpretation of data: Dickson, Schwartz, Keohan, D’Angelo, Gounder, Chi, Antonescu, Landa, Qin, Crago, Koff, Tap.
Drafting of the manuscript: Dickson, Schwartz, Antonescu, Tap.
Critical revision of the manuscript for important intellectual content: Dickson, Schwartz, Keohan, D’Angelo, Gounder, Chi, Landa, Qin, Crago, Singer, Koff, Tap.
Statistical analysis: Dickson, Schwartz, Landa, Qin.
Obtained funding: Dickson, Schwartz, Tap.
Administrative, technical, or material support: Dickson, Schwartz, Keohan, Antonescu, Landa, Tap.
Study supervision: Dickson, Schwartz, Singer, Tap.
Conflict of Interest Disclosures: Drs Dickson, Singer, and Schwartz acted as consultants for Pfizer. Drs Dickson, Koff, Singer, Crago and Schwartz have a planned patent on a companion diagnostic for CDK4 inhibitors. No other conflicts are reported.
Funding/Support: Palbociclib and partial funding of the clinical trial were supplied by Pfizer. This study was also supported in part by the National Cancer Institute and the National Institutes of Health through the Soft Tissue Sarcoma Program Project grant (grant No. P01 CA047179 [G.K.S., C.R.A., S.S.]) and the SPORE in Soft Tissue Sarcoma (grant No. P50 CA140146 [G.K.S., P.C., C.R.A., L.-X. Q, S.S., A.K., W.D.T.]).
Role of the Funder/Sponsor: The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Previous Presentations: Partial results from this study were presented at the 2013 Annual Meeting of the American Society for Clinical Oncology; May 31, 2013-June 4, 2013; Chicago, Illinois; and the 2013 Congress of the European Society for Medical Oncology; September 27, 2013-October 1, 2013; Geneva, Switzerland.
Additional Contributions: We thank Marietta Ezeoke, BA, for assistance in data collection. Ms Ezeoke was compensated as a paid research study assistant at Memorial Sloan Kettering Cancer Center.
Create a personal account or sign in to: