Palbociclib Demonstrates Disease Control in Advanced Chordoma Harboring p16, CDKN2A Loss

Data from the single-arm, phase 2 NCT PMO-1601 trial (NCT03110744)—which evaluated palbociclib (Ibrance) for the treatment of patients with advanced chordoma harboring p16 and/or CDKN2A loss, as well as retained CDK4/6 and RB1 expression—highlight the potential use of CDK4/6 inhibition as part of molecularly tailored combination therapies for this patient population.1

Findings published in ESMO Open showed that the study met its primary end point of disease control rate (DCR) after 6 cycles of therapy. At a median follow-up of 28.0 months (95% CI, 20.0-48.6), evaluable patients (n = 28) achieved a DCR of 39% (95% CI, 21.5%-59.4%). Notably, no responses were observed. Best response per RECIST 1.1 criteria comprised disease stabilization over several months (n = 11); stable disease for the first 3 months, followed by disease progression (n = 7); and rapid disease progression (n = 7). Three patients achieved long-term stable disease with respective durations of 19, 27, and 42 months.

Palbociclib also generated a median progression-free survival (PFS) of 5.6 months (95% CI, 3.2-11.1) and a median overall survival (OS) of 24.6 months (95% CI, 11-not reached).

“The molecular heterogeneity of the disease suggests that combination therapies could be more effective, but there is clearly a continuing need for more molecular mechanism-aware therapies or combination strategies, as well as better patient selection,” lead study author Maria-Veronica Teleanu, MD, head of the Department of Translational Medical Oncology at the National Center for Tumor Diseases Heidelberg and German Cancer Research Center in Germany, and colleagues wrote in a publication of the data.

Study Design

No drugs are currently approved for the treatment of patients with locally advanced or metastatic chordoma. Although chemotherapy and repurposed targeted agents are routinely used in this setting, antitumor activity is modest.

Study authors noted that approximately 14% of patients with advanced chordoma harbor alterations that have targeted therapies currently approved by the FDA. Notably, the tumor suppressor p16 is inactivated in more than half of patients in this population, resulting in the activation of the CDK4/6-RB pathway and fueling the rationale for evaluating palbociclib in this context. Palbociclib is currently approved by the FDA for the treatment of select patients with hormone receptor–positive, HER2-negative advanced breast cancer.2

The nonrandomized, open-label, multicenter NCT PMO-1601 study enrolled patients at least 18 years old with locally advanced or metastatic chordoma that was not amenable to curative-intent treatment with surgery or radiation.1 Disease progression per RECIST 1.1 criteria on the last line of treatment was not required. Patients needed to have p16 or CDKN2A loss per immunohistochemistry (IHC) or genomic analysis, along with CDK4/6 and RB1/pRB1S780 expression per IHC or transcriptomic analysis. Other key inclusion criteria included at least one measurable lesion per RECIST 1.1 criteria, adequate organ function, and an ECOG performance status 2 or less.

All patients received palbociclib at 125 mg once per day on days 1 to 21 of each 28-day cycle.

DCR by RECIST 1.1 criteria after 6 cycles of palbociclib served as the trial’s primary end point. Secondary end points comprised overall response rate, PFS, and OS. Exploratory end points included correlative biomarker studies and patient-reported outcomes.

Enrolled patients had a median age of 59 years (range, 31-84). Most patients were male (75%), had an ECOG performance status of 1 (50%), and had conventional histology (96%). Primary tumor sites comprised the sacrum (58%), mobile spine (28%), and skull base (14%). TNM classification included stage I (7%), stage III (7%), stage IV (68%), and not available (18%).

The median time from diagnosis was 7.7 years (range, 0-28), and patients received a median of 1 prior line of therapy (range, 0-5). Prior treatments included surgery (96%), radiation (96%), and systemic therapy (75%). Previous systemic treatments included imatinib (Gleevec; n = 16), erlotinib (Tarceva) with or without bevacizumab (Avastin; n = 3), sirolimus with or without imatinib (n = 5), sorafenib (Nexavar; n = 3), sunitinib (Sutent; n = 1), doxorubicin/ifosfamide (n = 1), and pembrolizumab (Keytruda; n = 1). Best response to the last line of therapy (n = 21) included partial response (5%), stable disease (24%), progressive disease (52%), and missing (14%).

Additional Efficacy and Safety Data

Findings also showed that among pretreated patients (n = 21), the median PFS was 5.5 months compared with 9.1 months in treatment-naive patients (n = 7; P = .57). The median OS was 34.0 months vs 17.0 months, respectively (P = .91).

Any-grade treatment-related adverse effects (TRAEs) were reported in 96.4% of patients, including 39.2% of patients who experienced grade 3 TRAEs. TRAEs led to dose interruptions or reductions occurred in 8 patients. One patient discontinued treatment due to grade 3 neutropenia.

The most common any-grade TRAEs reported in at least 10% of patients included neutropenia (57.1%), leukopenia (39.3%), anemia (21.4%), thrombocytopenia (21.4%), fatigue (21.4%), infections (17.9%), nausea (17.9%), headache (10.7%), and dry skin (10.7%).

References

1. Teleanu MV, Heilig CE, Pirmann S, et al. CDK4/6 inhibition in advanced chordoma: final results of the NCT PMO-1601 trial. ESMO Open. 2025;10(7):105498. doi:10.1016/j.esmoop.2025.105498
2. Ibrance. Prescribing information. Pfizer. April 2025. Accessed August 27, 2025. https://labeling.pfizer.com/showlabeling.aspx?id=2191