Abstract
Background
Well-differentiated (WD) and dedifferentiated (DD) liposarcomas (LPS) are characterized by cyclin-dependent kinase (CDK)4 and mouse double minute 2 homolog (MDM2) amplification. Palbociclib, a selective CDK4/6 inhibitor, demonstrated promising activity in prior phase II trials and is included in the National Comprehensive Cancer Network Compendium for LPS. However, long-term overall survival (OS) data remain limited.
Patients and methods
Patients with advanced WD/DD LPS were enrolled in two non-randomized phase II trials. Cohort A received palbociclib 200 mg (14 days on, 21-day cycle); cohort B received 125 mg (21 days on, 28-day cycle). Kaplan–Meier methods were used to estimate progression-free survival (PFS) and OS. Baseline factors and subsequent anticancer therapies were evaluated for association with outcomes.
Results
Among 90 patients, 88 were assessable for PFS. Median follow-up was 3.12 years (cohort A) and 2.59 years (cohort B). Median PFS was 4.2 and 4.1 months, and median OS was 26.0 and 24.2 months in cohorts A and B, respectively. One- and two-year OS rates exceeded 70% and 50%, respectively, across cohorts. Patients with pure WD histology (n = 15) had longer PFS (hazard ratio 0.53, P = 0.037) but no OS difference. Cadherin 18 (CDH18) expression on baseline tumor tissue was associated with improved PFS (P = 0.007) and OS (P = 0.003). After treatment, 39% underwent surgery and 46% received additional systemic therapy.
Conclusions
This study provides the longest prospective OS data for palbociclib in WD/DD LPS. CDK4/6 inhibition remains a relevant treatment option, especially for patients unsuitable for cytotoxic therapy. CDH18 expression was associated with clinical outcomes and represents an exploratory biomarker signal that warrants independent validation in future prospective, biomarker-focused studies.
Key words: liposarcoma, overall survival, prospective clinical trial, CDH18, biomarker discovery, CDK4/6 inhibition
Highlights
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This study provides long-term OS data from prospective palbociclib trials in WD/DD LPS.
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CDK4/6 inhibition remains clinically relevant in advanced LPS.
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CDH18 expression is associated with survival outcomes.
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CDH18 represents an exploratory biomarker requiring validation.
Introduction
Liposarcomas (LPS) are among the most common histologic subtypes of adult soft-tissue sarcoma.1 Two subtypes, well-differentiated (WD) and dedifferentiated (DD), are characterized by amplification of the cyclin-dependent kinase (CDK)4 and mouse double minute 2 homolog (MDM2) oncogenes.2,3 Both WD LPS and DD LPS are relatively insensitive to chemotherapy, and few effective treatment options exist for patients with unresectable or metastatic disease.4 Surgery is often employed as a treatment strategy but is rarely curative.5,6 Doxorubicin or doxorubicin-based combination regimens remain the standard in the first-line setting, though substantial tumor shrinkage with chemotherapy is uncommon.7, 8, 9, 10 Given their unique biology, our group previously evaluated the role of CDK4/6 inhibitor (CDK4/6i) as a treatment for WD/DD LPS.
In the phase II trial of the selective CDK4/6i palbociclib (PD0332991) in advanced WD/DD LPS, patients with CDK4 amplification and intact retinoblastoma protein (RB1) expression were treated with palbociclib [200 mg per os (p.o.) daily for 14 days, in a 21-day cycle]. This study demonstrated that selective CDK4 inhibition is a promising treatment for liposarcoma, with 66% of patients achieving prolonged progression-free survival (PFS) at 12 weeks, which was the primary endpoint of the trial.11
Concerns about toxicity at the higher 200-mg dose prompted a second cohort of patients to be enrolled in a follow-up phase II trial, using a lower dose of palbociclib (125 mg p.o. daily for 21 days, in a 28-day cycle), a regimen that is Food and Drug Administration-approved for breast cancer. This second trial confirmed the efficacy of CDK4 inhibition, with PFS rates of 57.2% at 12 weeks and 41.6% at 18 weeks in this chemotherapy-resistant population.12 Across both studies, the median PFS was 18 weeks. Together, these trials provided critical proof of concept for targeting the CDK4–cyclin D–RB pathway in WD/DD LPS, which resulted in palbociclib being included in the National Comprehensive Cancer Network Compendium for the treatment of liposarcoma.
Since these initial trials, many patients with DD LPS have been treated with palbociclib as part of standard of care. Additionally, abemaciclib, a more potent CDK4/6i, has shown greater promise. In a phase II trial conducted by Gleason et al., abemaciclib demonstrated a median PFS of 33 weeks in patients with DD LPS.13 These encouraging results are now being further investigated in an ongoing randomized, double-blind phase III trial of abemaciclib in DD LPS.14
To provide additional insights into the long-term outcomes from these phase II trials of palbociclib, we now report overall survival (OS) analysis based on the data cut-off of 15 August 2024, ∼8.5 years after the last patient was enrolled. This analysis includes exploratory evaluations of baseline and post-treatment factors beyond assigned study treatment and their association with OS and PFS.
Patients and methods
Study design
Patients with advanced WD/DD LPS were enrolled in two non-randomized phase II trials of palbociclib: cohort A received 200 mg daily for 14 days in a 21-day cycle, while cohort B received 125 mg daily for 21 days in a 28-day cycle (Clinical trial information: NCT01209598). The study design, eligibility criteria, and assessments have been fully described previously.11,12 Eligible patients were patients 18 years and older with advanced WD/DD LPS, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and measurable disease by RECIST 1.1. Both sexes were eligible, and sex, age, and ECOG performance status were recorded as baseline demographics.
All patients in the cohort A dosing group were required to have CDK4 amplification and intact retinoblastoma protein expression by immunohistochemistry (IHC). The cohort B dosing group was subdivided into an initial and expansion cohort. In the initial cohort, patients were required to have received at least one prior systemic therapy, while this was not mandatory for patients in the expansion cohort. Additionally, the initial cohort required CDK4 amplification, confirmed by FISH, and retinoblastoma protein expression by IHC, as described previously.11 Given the high prevalence of CDK4 amplification in WD/DD LPS, all tested patients were positive, leading to the removal of this requirement for the expansion cohort.
Cadherin 18 (CDH18) expression was assessed by IHC on formalin-fixed, paraffin-embedded tumor resections, as previously described.15 Sections (200-600 mm2) were stained with a mouse monoclonal antibody to CDH18 (Abnova, Taipei City, Taiwan, H00001016-M01), with specificity validated in CDH18 knockout cell lines. Staining was scored in a blinded pathology review. Tumors were classified as CDH18-positive if >80% of tumor cells showed cytoplasmic staining throughout the section. Samples with mixed positive and negative tumor cell populations were categorized as equivocal, and internal inflammatory or vascular cells served as positive and negative controls, respectively.
The trials were non-randomized and single-arm; no allocation or blinding procedures were used. The protocol was approved by the institutional review board of the Memorial Sloan Kettering Cancer Center and all patients provided written informed consent.
Endpoints and assessments
OS was defined as the time from treatment initiation to death and censored if alive at last follow-up. Disease-specific survival (DSS) was defined as the time from treatment initiation to death from disease and censored at death from other causes or last follow-up. PFS was defined as the time from treatment initiation to clinical or radiographic progression and censored at trial end. This was an intent-to-treat analysis and all patients enrolled were included in the OS and DSS analysis. Patients were assessable for PFS if they completed the first scan at 6 weeks on trial. Attrition, including patients who discontinued early or were lost to follow-up, was recorded.
We next sought to describe how subsequent anticancer therapies affected outcomes. It should be noted that these are exploratory and not pre-specified in the protocol and collected after trial completion. Patient history and treatment history following the clinical trial were collected and analyzed. A subgroup of patients had recurrence and underwent resection after trial completion. In this subset, a second OS outcome was defined as the time from resection to death or last follow-up.
Statistical analysis
The original study was powered to evaluate the primary endpoint of 12-week PFS, with a planned sample size of 28 patients. The current analysis focuses on secondary outcomes, including OS and PFS. These endpoints were not formally powered and are presented descriptively.
Categorical variables were summarized using count and percentage and compared between patient cohorts using Fisher’s exact test. Continuous variables were summarized using median and interquartile range (IQR) and compared between cohorts using the Wilcoxon rank sum test. Kaplan–Meier methods were used to illustrate and describe the survival outcomes. Cox proportional hazard models were used to test the association between survival outcomes and clinical factors. SAS 9.4 was used for all analysis. All tests were two-sided and P < 0.05 was considered significant.
Results
Patient characteristics
In the initial cohort treated with palbociclib 200 mg (cohort A), 51 patients consented to the protocol between October 2010 and November 2011 (Supplementary Figure S1, available at https://doi.org/10.1016/j.esmoop.2026.106899). Cyclin amplification and intact RB expression were required for eligibility in cohort A. CDK4 amplification was detected in 44 (92%) of 48 tumors tested. Of these, 41 patients met the inclusion criteria and were eligible for treatment after confirmation of intact RB expression; the remaining 7 patients were excluded due to clinical deterioration, technical failure in RB testing, or patient choice. Of the eligible patients, 30 started study treatment. One patient withdrew consent after experiencing grade 3 nausea, diarrhea, and fatigue during the first treatment cycle and did not have a repeat computed tomography scan, rendering them unassessable for PFS.
In cohort B (palbociclib 125 mg), 60 patients were enrolled between December 2011 and January 2014, split evenly between two groups. The first group (n = 30) required at least one prior systemic therapy and CDK4 amplification, while the second group (n = 30) had no such requirements; 73% of the expansion group patients had received no prior systemic therapy, and only five patients underwent CDK4 amplification testing. One patient withdrew consent before the first radiographic assessment, rendering them unassessable for PFS.
In both cohorts, the majority of patients had abdominal or retroperitoneal disease (97% in each). For cohort A, 86.7% of patients had DD subtype, whereas 78% of patients in cohort B had DD subtype. Median age was 68 years (IQR 56-74 years) in cohort A and 61 years (IQR 52-69 years) in cohort B. ECOG performance status was similar across cohorts, with a median score of 0 (range 0-1) (Table 1).
Table 1.
Baseline patient characteristics
| Cohort A |
Cohort B |
P value | ||
|---|---|---|---|---|
| 200 mg (n = 30) | 125 mg (n = 60) | Total (N = 90) | ||
| Age, years | ||||
| Median (IQR) | 67.5 (56.0-74.0) | 60.5 (52.0-69.0) | 62.5 (52.0-71.0) | 0.241 |
| Sex, n (%) | ||||
| Female | 16 (53.3) | 29 (48.3) | 45 (50.0) | 0.823 |
| Male | 14 (46.7) | 31 (51.7) | 45 (50.0) | — |
| Histology, n (%) | ||||
| DDa | 26 (86.7) | 49 (81.7) | 75 (83.3) | 0.765 |
| WDb | 4 (13.3) | 11 (18.3) | 15 (16.7) | — |
| Primary site, n (%) | ||||
| ET | 1 (03.3) | 2 (3.3) | 3 (3.3) | >0.95 |
| RP | 29 (96.7) | 58 (96.7) | 87 (96.7) | — |
| ECOG, n (%) | ||||
| 0 | 20 (66.7) | 52 (86.7) | 72 (80.0) | 0.048c |
| 1 | 10 (33.3) | 8 (13.3) | 18 (20.0) | — |
| Prior treatment categories, n (%) | ||||
| 0 | 0 (0.0) | 22 (36.7) | 22 (24.4) | <0.001c |
| 1 | 17 (56.7) | 29 (48.3) | 46 (51.1) | — |
| 2+ | 13 (43.3) | 9 (15.0) | 22 (24.4) | — |
| CDH18 status, n (%) | ||||
| Equivocal | 1 (6.3) | 4 (12.5) | 5 (10.4) | 0.905 |
| Negative | 4 (25.0) | 9 (28.1) | 13 (27.1) | — |
| Positive | 11 (68.8) | 19 (59.4) | 30 (62.5) | — |
| Unknown | 14 (46.7) | 28 (46.7) | 42 (46.7) | — |
DD, dedifferentiated; ECOG, Eastern Cooperative Oncology Group; ET, extremity; IQR, interquartile range; RP, retroperitoneal; WD, well-differentiated.
Represents WD/DD and pure DD histology.
Represents pure WD histology.
Statistical signficance, P < 0.05.
Efficacy
Among the 90 enrolled patients, 88 were assessable for PFS: 29 from cohort A and 59 from cohort B. At the data cut-off on 15 August 2024, 79 patients had died, including 28 in cohort A and 51 in cohort B. The median duration of follow-up was 3.12 years in cohort A and 2.59 years in cohort B. All 90 patients were assessable for OS. The OS benefit was consistent across cohorts. The Kaplan–Meier estimate of the median OS was 26 months [95% confidence interval (CI) 17.2-40.1 months] in cohort A and 24.2 months (95% CI 17.5-38.5 months) in cohort B (Figure 1). The estimated 1-year and 2-year OS rates were 73% (95% CI 0.54% to 0.86%) and 53% (95% CI 0.34% to 0.69%) in cohort A and 71% (95% CI 0.57% to 0.81%) and 50% (95% CI 0.37% to 0.62%) in cohort B, respectively. Updated PFS analyses also remained consistent with the primary results of the trial: the median PFS was 4.2 months (95% CI 3.1-6.9 months) in cohort A and 4.1 months (95% CI 2.7-5.4 months) in cohort B (Figure 1A). The PFS rates at 6 months and 1 year were 38% (95% CI 0.21% to 0.55%) and 17% (95% CI 0.06% to 0.33%), respectively, in cohort A, compared with 33% (95% CI 0.21% to 0.45%) and 15% (95% CI 0.07% to 0.25%), respectively, in cohort B.
Figure 1.
Progression free survival and overall survival. Updated (A) PFS and (B) OS in the intent-to-treat population of both cohorts. PFS is defined as time from treatment initiation to progression, and patients were censored at off-study date. Two patients who were not assessable for response were removed from this analysis. OS is defined as time from treatment initiation to death and censored at last follow-up. CI, confidence interval; OS, overall survival; PFS, progression-free survival.
Across both cohorts, patients with pure WD histology demonstrated better PFS [hazard ratio (HR) 0.53, 95% CI 0.30-0.96, P = 0.037], though there was no significant difference in OS between the two histologic subtypes (HR 0.64, 95% CI 0.35-1.16, P = 0.142) (Figure 2A and B). However, pure WD histology (15 patients) may have been underrepresented in comparison to mixed or DD histology in the study population. CDH18 positivity on baseline tissue was associated with significantly improved PFS (CI 0.19-0.79, P = 0.009) and OS (CI 0.15-0.63, P = 0.001) (Figure 3). No other baseline factors were significantly associated with OS in the univariate analysis (Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2026.106899).
Figure 2.
Outcomes by histologic subtype. Updated (A) PFS and (B) OS in the intent-to-treat population by histologic subtype. CI, confidence interval; DD, dedifferentiated; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; WD, well-differentiated.
Figure 3.
Outcomes by baseline CDH18 status. (A) PFS and (B) OS in the intent-to-treat population by CDH18 status. Patients positive of CDH18 in pretreatment samples had significantly longer PFS and OS. CI, confidence interval; OS, overall survival; PFS, progression-free survival.
Subsequent anticancer therapies
Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2026.106899, summarizes subsequent anticancer local and systemic therapies patients underwent upon discontinuation of palbociclib. After discontinuing palbociclib, 35 patients underwent surgical resection (Supplementary Table S3, available at https://doi.org/10.1016/j.esmoop.2026.106899). R0 or R1 resection was achieved in 20 patients. Among patients undergoing surgery, median OS from first resection after discontinuation of palbociclib was 30.0 months (95% CI 4.6-114.5 months) in cohort A and 54.8 months (95% CI 17.0-88.4 months) in cohort B (Figure 4).
Figure 4.
Overall survival from resection. OS from resection is defined as time from resection to death or last follow-up. There was no significant different across both groups. CI, confidence interval; OS, overall survival.
Radiotherapy (RT) following discontinuation of palbociclib was uncommon, with only six patients across both cohorts receiving RT.
Subsequent systemic anticancer therapy was administered to 13 patients in cohort A and 28 patients in cohort B. Supplementary Table S4, available at https://doi.org/10.1016/j.esmoop.2026.106899, summarizes the systemic therapies received. Patients underwent a median of 2 lines of post-palbociclib therapy (range 1-11). Most patients received at least one cytotoxic chemotherapy agent (10 patients in cohort A and 25 patients in cohort B). Participation in other investigational, immunomodulatory, or targeted therapies was also frequent, occurring in 8 patients in cohort A and 30 patients in cohort B.
Discussion
This study provides the longest-reported OS data from prospective trials evaluating CDK4/6 inhibition in WD/DD LPS. The 1-year and 2-year OS rates reinforce that a subset of patients achieve prolonged survival, underscoring the continued relevance of CDK4/6i as a viable treatment option. These outcomes compare favorably with historical benchmarks for this population, where retrospective studies have reported a median OS of ∼15 months with a variety of chemotherapy regimens.8 Our findings reaffirm the role of palbociclib in WD/DD LPS, providing disease control in a malignancy with limited systemic options.
Additionally, this study addresses a critical gap in the field, where most available OS data are derived from retrospective analyses or basket trials rather than dedicated prospective studies. A real-world study of palbociclib in LPS reported a median OS of 23.2 months among patients who did not undergo surgery. This is remarkably similar to the median OS observed in our trial, despite a shorter median PFS.16 This discrepancy may reflect differences in patient selection, disease burden, or post-treatment management, highlighting the heterogeneity of clinical outcomes in this population. These findings emphasize the importance of prospective OS data and the challenges of translating trial findings into broader clinical practice.
Patients with pure WD histology demonstrated significantly longer PFS despite being underrepresented in the study. However, OS did not differ significantly between pure WD and DD subtypes, suggesting potential confounding factors such as the natural indolence of WD disease and selection bias favoring treatment of more aggressive cases. WD histology is known to confer a favorable prognosis, with superior survival rates compared with DD LPS, which has the worst outcomes among LPS.17 This highlights the need for further molecular and clinical characterization of WD patients who might benefit from CDK4/6 inhibition.
Interestingly, CDH18 positivity in baseline tissue was found to be positively associated with OS. Prior preclinical and translational work has implicated CDH18 in the regulation of therapy-induced senescence, the dominant mechanism by which palbociclib exerts antitumor effects in LPS. Specifically, CDH18 sequesters PDZ and LIM domain 7 (PDLIM7) away from MDM2, enabling MDM2 turnover and progression from quiescence to irreversible senescence. CDH18 positivity was associated with improved PFS and OS, supporting its potential as a putative predictive biomarker.15 Our findings corroborate these data, and suggest that IHC for CDH18 may serve as a useful predictive and prognostic marker. Independent prospective validation will be required to clarify its biological relevance and potential utility as a prognostic factor or stratification variable in future biomarker-focused trials.
Due to modest systemic response rates, surgery plays a central role in the management of LPS. In our study, 35 patients ultimately underwent surgical resection following disease progression, with R0/R1 resection achieved in 20 patients. While prior studies suggest macroscopically complete resection improves DSS, margin status was not a pre-specified endpoint in this study.18,19 Furthermore, it is unlikely that palbociclib monotherapy facilitated resectability given the modest objective response rates previously reported.11,12
RT use was limited in our cohort, partly reflecting institutional practice patterns and the high prevalence of retroperitoneal disease, where palliative RT is less commonly pursued. Prior studies have suggested improved local control rates with RT in select liposarcoma subtypes, but without improvement in OS.20, 21, 22 Further studies are needed to clarify the utility of RT in advanced or recurrent disease.
Additionally, the high rate of subsequent systemic therapy uses post-palbociclib indicates that CDK4/6i are being integrated into broader treatment paradigms rather than being used as definitive therapy. Notably, many patients were enrolled in investigational or targeted therapy trials, emphasizing the growing interest in rational combination strategies with CDK4/6i.
Emerging therapeutic strategies seek to improve upon the efficacy of CDK4/6i in LPS. Preclinical studies have identified synergistic potential between CDK4/6i and immune checkpoint inhibitors, such as anti-PD-1 therapy, through enhanced T-cell activation, increased antigen presentation, and modulation of the tumor microenvironment.23,24 This combination is currently being evaluated in an ongoing clinical trial (NCT04438824), with early results indicating promising responses in a subset of patients.25
Abemaciclib, a more potent CDK4/6i with continuous dosing, has demonstrated a longer median PFS of 33 weeks in a phase II trial for DD LPS.13 These findings highlight the potential for optimizing CDK4/6i in this disease. Mechanistic insights from prior studies, including the role of MDM2 and mitogen-activated protein kinase pathways in mediating resistance, provide a strong rationale for exploring combination strategies such as MDM2 and mitogen-activated protein kinase kinase (MEK) inhibitors.13,26,27 A phase III randomized trial of abemaciclib (NCT04967521) is ongoing, which will further clarify its role in the treatment landscape of LPS.14
In conclusion, this study provides long-term survival outcomes from prospective trials of palbociclib in WD/DD LPS, reinforcing the continued role of CDK4/6i in the treatment paradigm. While efficacy remains modest, palbociclib offers a well-tolerated alternative to chemotherapy, and its integration into multimodal treatment strategies continues to evolve. The observed association between CDH18 expression and survival outcomes represents an exploratory biomarker signal that warrants independent prospective validation. Future efforts should focus on biomarker-driven approaches and combination therapies to optimize outcomes for patients with this heterogeneous and challenging malignancy.
Declaration of generative AI and AI-assisted technologies in the writing process
During the preparation of this manuscript, the authors used generative artificial intelligence (AI) tools to enhance clarity and readability. After use of these tools, the corresponding author carefully reviewed and edited the text and assumes full responsibility for the final content.
Acknowledgments
Funding
This work was supported in part through the NIH/NCI Cancer Center Support Grant [grant number P30CA008748], the Kristen Ann Carr Fund, the Memorial Sloan Kettering SPORE in Sarcoma, and the MSK T32 Investigational Cancer Therapeutics Training Program. The funding sources had no role in study design, data collection, analysis, interpretation, or writing of the manuscript.
Disclosure
AK reports a relationship with Atropos Therapeutics, Inc. that includes: equity or stocks. WDT reports a relationship with Atropos Therapeutics, Inc. that includes: equity or stocks. All other authors have declared no conflicts of interest.
Data sharing
De-identified patient-level data and supporting materials are available upon reasonable request to the corresponding author, subject to data-sharing agreements and institutional approval.
Supplementary data
References
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