Abemaciclib Demonstrates Promising Clinical Activity in Dedifferentiated Liposarcoma

Mark A. Dickson, MD

Results from a phase II trial of abemaciclib (Verzenio) presented at the 2018 CTOS Annual Meeting showed that the majority of patients (74%) with dedifferentiated liposarcoma remained progression free at 12 weeks following abemaciclib treatment.¹

Dedifferentiated liposarcoma is the least common subtype of liposarcoma and it usually arises from a well-differentiated liposarcoma (WDLS). These tumors are mostly seen in adults and tend to grow more aggressively than low-grade WDLS. The metastasis rate in dedifferentiated liposarcoma ranges from 13% to 47%.

Abemaciclib is a selective oral ATP-competitive inhibitor of cyclin dependent kinases (CDKs) 4 and 6.

“Abemaciclib targets CDK4 amplification, which occurs in more than 90% of well-differentiated and dedifferentiated liposarcomas,” explained Mark A. Dickson, MD, of Memorial Sloan Kettering Cancer Center in New York. “In liposarcoma, CDK4 is highly amplified by more than a 10-fold increase compared to normal adipocytes.”

Abemaciclib is approved by the FDA for the treatment of patients with HR-positive, HER2-negative metastatic breast cancer, and has demonstrated tumor shrinkage in patients with lymphoma, breast, and lung cancer.  

This is the first trial of abemaciclib in liposarcoma.

This investigator-initiated, single-center, phase II trial (NCT02846987) evaluated the efficacy and safety of abemaciclib in patients with recurrent or metastatic dedifferentiated liposarcoma. Patients were required to have progressive disease confirmed by RESIST 1.1 within 6 months prior to study entry. Patients were allowed to have had any number, including none, of prior systemic therapies, and demonstration of CDK4 amplification upon enrollment was not required.

From August 2016 to June 2018, the trial enrolled 24 patients and treated 23 patients with abemaciclib at 200 mg twicedaily. The patients’ median age was 62 years (range, 39-88) and 59% were male. Half of the patients had not received any prior treatment; 29% had received 1 regimen and 21% of patients had received ≥2 prior systemic treatments that included doxorubicin, gemcitabine, docetaxel, and other chemotherapy. The location of the primary tumor was abdomen or retroperitoneum in 88% of patients and the extremity in 12%. The median degree of CDK4 amplification was an 8.6-fold (range, 3.5-17) change from the norm. 

Biopsies were obtained before and after 4 to 6 weeks of treatment and tumor restaging was done every 6 weeks. Patients who had progressive disease or serious toxicity were discontinued from treatment, those who achieved a response or had stable disease continued treatment until progression or toxicity.

The primary study endpoint was progression-free survival (PFS) at 12 weeks; the demonstration of 15 or more patients being progression free at 12 weeks was considered a positive result.

In fact, 17 of the first 23 patients treated with abemaciclib reached the week 12 progression-free mark; the 12-week PFS rate was 74% (95% CI, 58%-94%). The median PFS was 30 weeks. Tumor reduction by RESIST was observed in 11 patients. One partial response (PR) was observed, providing a response rate of 4%. At data cut off, 9 patients maintained stable disease, including the 1 PR.

Dickson noted that these results compared well to those reported in prior phase II trials with another CDK4 inhibitor, palbociclib (Ibrance), which demonstrated response rates of 2% to 3% and a median PFS of 18 weeks. The 12-week PFS rates in these trials were 57% and 66%.^2,3

“This study met its primary endpoint; patients with advanced progressive de-differentiated liposarcoma treated with abemaciclib demonstrated a favorable PFS rate at 12 weeks and some objective tumor response,” said Dickson.

Regarding toxicity, no grade ≥4 toxicities were observed. Grade 2 toxicities occurring in ≥20% of patients included anemia in 70%, neutropenia in 43%, thrombocytopenia in 39%, diarrhea in 26%, and fatigue in 22%. Grade 3 anemia was reported in 43% of patients and 22% of patients each reported grade 3 neutropenia and decreased lymphocyte count. No patients discontinued treatment.

“Analysis of paired tumor biopsies is ongoing to determine predictors of clinical benefit with abemaciclib,” Dickson commented.

References:

1. Dickson MA, D’Angelo S, Gounder M, et al. Phase 2 study of the CDK4 inhibitor abemaciclib in dedifferentiated liposarcoma. Presented at: the 2018 CTOS Annual Meeting; November 14-17, 2018; Rome, Italy. Paper 020.
2. Dickson MA, Tap WD, Keohan ML, et al. Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma.J Clin Oncol.2013;31(16):2024-2028. doi: 10.1200/JCO.2012.46.5476.
3. Dickson MA, Schwartz GK, Keohan ML, et al. Progression-Free Survival Among Patients With Well-Differentiated or Dedifferentiated Liposarcoma Treated With CDK4 Inhibitor Palbociclib: A Phase 2 Clinical Trial.JAMA Oncol.2016;2(7):937-940. doi: 10.1001/jamaoncol.2016.0264.