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).

Abstract

11511 Background: CDK4/6 inhibitors showed a favorable progression-free survival (PFS) in DD LPS, a sarcoma bearing 12q 13-15 amplicon that implies CDK4 amplification. The median PFS was 4 and 7 months (m) 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: Progressing pretreated advanced soft tissue sarcoma, excluding DD LPS, or osteosarcoma adult patients (pts), 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-m 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 pts had a PFS > 6 m from 21 evaluable pts. 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. Results: A total of 214 pts 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%) pts with favorable mRNA profile from pre and screening, respectively. Twenty-two pts 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 m (0.4-23.3), the median PFS was 4.2 m (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 pts (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 the best response. Patients with CDK4 expression above the median value had significantly longer mPFS in the univariate analysis: 5.9 m (95% CI 1.4-10.4) vs 1.9 m (95% CI 0.6-3.2), p = 0.046; and longer OS: 15.5 m (95% CI 6.8-24.3) vs 10.6 m (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. Conclusions: Palbociclib showed to be effective in a wide variety of sarcoma subtypes, other than DD LPS, selected by CDK4/CDKN2A biomarkers. Clinical trial information: NCT03242382.

Emerging roles of long non-coding RNAs in osteosarcoma

“…Currently, the standard treatment for OS is surgery to remove the tumor followed by chemotherapy. Targeted drugs are being developed to treat OS, but none have been approved yet ( Martin Broto et al, 2022 ). Chemoresistance resistance is frequently observed during OS treatment.…”

Glutaminase as a metabolic target of choice to counter acquired resistance to Palbociclib by colorectal cancer cells

“…Among these, Palbociclib (PD0332991) was the first-in-class drug to show promising results in phase III studies (Beaver et al, 2015;Marra and Curigliano, 2019;O'Leary et al, 2016). More recently, Palbociclib and other CDK4/6 inhibitors (CDK4/6i), in a variety of combinations, have shown efficacy in other cancer types, including colorectal carcinoma (Bride et al, 2022;Coffman et al, 2022;de Kouchkovsky et al, 2022;Gleason et al, 2024;Kase et al, 2024;Lee et al, 2023;Lee et al, 2016;Lelliott et al, 2021;Mao et al, 2021;Martin-Broto et al, 2023;Movva et al, 2024;Ngamphaiboon et al, 2024;Pek et al, 2017;Pesch et al, 2022;Raetz et al, 2023;Selby et al, 2023;Sorokin et al, 2022), particularly in tumors bearing genetic or epigenetic alterations underlying an upregulated G1-S cell cycle transition (Mao et al, 2021;Pesch et al, 2022). In addition to a direct effect on cancer cell survival, CDK4/6i have been shown to promote anti-tumor immune responses (Lelliott et al, 2021;Petroni et al, 2020).…”

Role of CDK4 as prognostic biomarker and synergistic effect of its inhibition in dedifferentiated liposarcoma sequential treatment

“…Recent real word retrospective analysis conducted by The University of Texas MD Anderson Cancer Center on 61 retroperitoneal WDLPS and DDLPS treated with palbociclib monotherapy after surgery showed no improvement in overall survival [13]. After these disappointing results the phase II palbosarc study has investigated the activity of palbociclib in advanced sarcoma overexpressing CDK4 gene excluding DDLPS showing that palbociclib could be effective in a wide variety of sarcoma histotypes (NCT03242382) [14]. Recent study has highlighted the promising role of adjuvant palbociclib in delaying recurrence in completely resected retroperitoneal liposarcoma [15].…”