(P 161) PALBOSARC: A PHASE II TRIAL OF PALBOCICLIB IN ADVANCED SARCOMA OVEREXPRESSING CDK4 GENE EXCLUDING DEDIFFERENTIATED LIPOSARCOMA (DD LPS): A STUDY FROM THE SPANISH GROUP FOR RESEARCH ON SARCOMA (GEIS).

Objective: CDK4/6 inhibitors showed a favorable progression-free survival (PFS) in dedifferentiated liposarcoma (DD LPS), a sarcoma bearing 12q 13-15 amplicon that implies CDK4 amplification. The median PFS was 4 and 7 months for palbociclib and abemaciclib, respectively. Preclinical experiments in 10 sarcoma cell lines and 6 PDX models, including only one DD LPS, showed higher efficacy of anti-CDK4 in cases with high expression of CDK4 and low expression of p16. This rationale supported the design of a phase II trial exploring palbociclib in a wide range of sarcomas, excluding DD LPS

Methods: Adult patients with progressing pretreated advanced soft tissue sarcoma (excluding DD LPS or low-grade osteosarcoma), whose tumors overexpressed CDK4 and underexpressed CDKN2A mRNA in a baseline mandatory biopsy, were enrolled. CDK4 and CDKN2A expression were assessed by qRT-PCR, using an external control as reference (Universal human reference RNA; Agilent Technologies). The primary endpoint was 6-month PFS rate. Minimax Simon’s two-stage with type 1 and 2 errors of 10%, and null and alternative hypothesis of H0 15%, H1 40%, 6-month PFS rates were specified. The study will warrant further investigation if 6 or more patients had a PFS > 6 months from 21 evaluable patients. Palbociclib was administered orally at 125 mg/ day 21 out of 28 days. Pre-screening intended to increase the probability of positive profile in the baseline biopsy. Potentially predictive biomarkers (mutations of TP53 and RB1, proteinic levels of CDK4, E2F1, Cyclin E and amplifications of CDK4) will be analyzed.

Results: A total of 214 patients with 236 CDK4/ CDKN2A determinations were assessed for enrolment; 141 for prescreening, in archive tumor sample, and 95 for screening, in a baseline biopsy. There were 38/141 (27%) and 28/95 (29%) patients with favorable mRNA profile from pre and screening, respectively. Twenty-two patients were enrolled with a median of previous systemic lines of 3 (1-5). There were 9 different sarcoma subtypes, including 2 osteosarcomas. With a median FU of 10 months (0.4-23.3), the median PFS was 4.2 months (95% CI 0.9-7.4), while the 6- and 12-m PFS rates were 30% (95% CI 9-51) and 18% (95% CI 12-48) respectively. From 19 evaluable patients (1 early death by COVID, 1 withdrew consent and for 1 it was too early to be assessed) 11 had stable disease (58%) and 8 progressed (42%) as their best response. Patients with CDK4 expression above the median value had significantly longer mPFS in the univariate analysis: 5.9 months (95% CI 1.4-10.4) vs 1.9 months (95% CI 0.6-3.2), p = 0.046; and longer OS: 15.5 months (95% CI 6.8-24.3) vs 10.6 months (95% CI 0-23.2), p = 0.047, respectively. The probability to find a positive profile in the screening was 29%, but this proportion increased up to 41% if in pre-screening had been positive. Biomarker analysis is currently ongoing

Conclusion: Palbociclib showed to be effective in a wide variety of sarcoma subtypes, other than DD LPS, selected by CDK4/CDKN2A biomarkers