1490MO - CDK4/6 inhibition in locally advanced/metastatic chordoma (NCT PMO-1601)

Background

Chordoma is a rare bone tumor with an unmet therapeutic need. In chordoma cell lines and patient biopsies, the p16 (cyclin-dependent kinase inhibitor 2a, encoded by CDKN2A) tumor suppressor is consistently inactivated, resulting in aberrant cyclin D-CDK4/6-RB pathway activity, which can be efficiently inhibited by the CDK4/6 inhibitor palbociclib (PMID 26183925).

Methods

Patients (pts) ≥18 years (yrs) with locally advanced or metastatic chordoma, at least one measurable tumor lesion per RECIST 1.1, ECOG PS 0–2, adequate organ function, loss of p16 (by immunohistochemistry [IHC]) or CDKN2A (by genomic analysis) and presence of CDK4/6 and RB1 (by IHC or RNA-seq) and not amenable to curative surgery or radiotherapy, are eligible. Palbociclib 125 mg q.d. is given in a 21-days-on/7-days-off schedule. Based on a Simon optimal 2-stage design, disease control rate (DCR) is the primary endpoint. Response is defined as complete response (CR), partial response (PR), or stable disease (SD) per RECIST 1.1 after 6 cycles. For sample size calculation, a poor or good response were assumed to be 10% and 25%, respectively (α, 5 %; β, 20%), resulting in a 1^st stage of 18 pts and, if ≥3 pts respond, study continuation to a total of 43 pts.

Results

Between 12/2017 and 04/2022, 26 pts (female, n=6; median age, 59 yrs [range, 31–84]) were enrolled. Primary chordoma sites were sacrococcygeal (n=14), skull base (n=4), and other parts of the spine (n=8). Palbociclib was well tolerated. Adverse events were mostly mild (CTC-AE °1–2) cytopenias; one CTC-AE °5 was recorded (neutropenic sepsis). The interim analysis revealed 6/18 pts (33%) with SD and none with PR or CR. Recruitment was continued in 11/2021 as initially planed. Median progression-free survival was 5.75 months (95% confidence interval [CI], 3.55–not reached), and the median number of applied cycles was 6 (range, 2–42). Overall survival after 2 yrs was 74% (95% CI, 56–97%). Correlative biomarker studies, including WGS/WES and RNA-seq, are ongoing.

Conclusions

This is the 1^st proof-of-concept trial in chordomas using a genomic marker to predict palbociclib activity. Therapy with palbociclib resulted in a DCR of 33% with manageable toxicity. Although no PR or CR were yet achieved, single-agent palbociclib showed anti-tumor activity.

Clinical trial identification

NCT03110744.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Pfizer, National Center for Tumor Diseases Heidelberg.

Disclosure

R.W. Hamacher: Other, Personal, Other: Lilly, Novartis; Financial Interests, Personal, Other: Lilly; Financial Interests, Personal, Invited Speaker: PharmaMar. S. Bauer: Financial Interests, Personal, Advisory Board, Recurring Advisory Role since 2017 in the context of clinical trial development: Deciphera; Financial Interests, Personal, Advisory Board, Advisory role in the context of clinical trial development: Blueprint Medicines; Financial Interests, Personal, Advisory Board, Advisory role for clinical trial development: Lilly; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board, Clinical trial developemnt: Daiichi-Sankyo; Financial Interests, Personal, Advisory Board, 2017: Plexxikon; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker, CME-related presentations: PharmaMar; Financial Interests, Personal, Advisory Board, Advisory role drug development: Roche; Financial Interests, Personal, Advisory Board, Advisory role drug development,: GSK; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Invited Speaker, PI for Enliven trial: Daiichii-Sankyo; Financial Interests, Institutional, Invited Speaker, Local PI for Avelumab Phase I trial: Roche; Financial Interests, Institutional, Invited Speaker, PI for Intrigue, Invictus and DCC-2618-Phase I trial; Lead PI for INtrigue trial, Scientific Committee for Invictus and Intrigue: Deciphera; Financial Interests, Institutional, Invited Speaker, PI for JGDJ trial Phase I Olaratumab plus Doxo/Ifos: Lilly; Financial Interests, Institutional, Invited Speaker, PI for Phase I trials cCGM097, HDM201, STI571-2103: Novartis; Financial Interests, Institutional, Invited Speaker, Local PI und national PI for Voyager and Navigator trial (BLU-285 / Avapritinib): Blueprint Medicines; Financial Interests, Institutional, Invited Speaker, PI (national) for Relatlimab (BMS-CA224-020): BMS; Financial Interests, Institutional, Invited Speaker, PI for IIT with ponatinib in GIST; research Grant (institutional for IIT): Incyte; Non-Financial Interests, , Advisory Role, Off-label committee: BfArm; Non-Financial Interests, , Invited Speaker, Founding Member of German Sarcoma Foundation: Deutsche Sarkomstiftung (German SarcomaFoundation). S. Fröhling: Financial Interests, Personal, Advisory Board: Bayer, Illumina, Roche; Financial Interests, Personal, Invited Speaker: Amgen, Eli Lilly, Illuminna, PharmaMar, Roche. R.F. Schlenk: Financial Interests, Institutional, Invited Speaker, Webinar: Astellas; Financial Interests, Personal, Advisory Board, Presentation: Pfizer; Financial Interests, Personal, Other, DMC: BergenBiO; Financial Interests, Personal, Advisory Board, Ad Board: Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker, Speaker: Abbvie; Financial Interests, Institutional, Advisory Board: Jazz; Financial Interests, Institutional, Funding, GnG Study: Pfizer; Financial Interests, Institutional, Funding, Q-HAM StudyQ-SOC Study: Daiichi Sankyo; Financial Interests, Institutional, Funding, TOP-ART Study: AstraZeneca, PharmaMar; Financial Interests, Institutional, Funding, PMO-1604 Study: Boehringer Ingelheim; Financial Interests, Institutional, Funding, PMO-1601 study: Pfizer. All other authors have declared no conflicts of interest.